Heterocycles that are inhibitors of IMPDH enzyme

ABSTRACT

Compounds of the formula  
                 
 
     wherein X 1  is C(O), —S(O)—, or —S(O) 2 —;  
     X 2  is CR 3  or N; X 3  is —NH—, —O—, or —S—;  
     X 4  is CR 4  or N; X 5  is CR 5  or N; and X 6  is CR 6  or N are useful as inhibitors of IMPDH enzyme. Thus, these compounds can be used as therapeutic agents for IMPDH-associated disorders.

[0001] This application claims priority from U.S. application Ser. No.60/199,420 filed Apr. 24, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to novel compounds which inhibitIMPDH, and to methods of making such compounds. The invention alsoencompasses pharmaceutical compositions containing these compounds. Thecompounds and pharmaceutical compositions of the invention areparticularly well suited for inhibiting IMPDH enzyme activity and,consequently, can be advantageously used as therapeutic agents forIMPDH-associated disorders. This invention also relates to methods forinhibiting the activity of IMPDH using the compounds of this inventionalone or in combination with other pharmaceutically active agents.

BACKGROUND OF THE INVENTION

[0003] Inosine monophosphate dehydrogenase (IMPDH) has been shown to bea key enzyme in the regulation of cell proliferation anddifferentiation. Nucleotides are required for cells to divide andreplicate. In mammals, nucleotides may be synthesized through one of twopathways: the de novo synthesis pathway or the salvage pathway. Theextent of utilization of each pathway is dependent on the cell type.This selectivity has ramifications with regard to therapeutic utility asdescribed below.

[0004] IMPDH is involved in the de novo synthesis of guanosinenucleotides. IMPDH catalyzes the irreversible NAD-dependent oxidation ofinosine-5′-monophosphate (“IMP”) to xanthosine-5′-monophosphate (“XMP”),Jackson et al., Nature 256:331-333 (1975).

[0005] IMPDH is ubiquitous in eukaryotes, bacteria and protozoa. Theprokaryotic forms share 30-40% sequence identity with the human enzyme.

[0006] Two distinct cDNA's encoding IMPDH have been identified andisolated. These transcripts are labeled type I and type II and are ofidentical size (514 amino acids). Collart et al., J. Biol. Chem.263:15769-15772 (1988); Natsumeda et al., J. Biol. Chem. 265:5292-5295(1990); and U.S. Pat. No. 5,665,583 to Collart et al. These isoformsshare 84% sequence identity. IMPDH type I and type II form tetramers insolution, the enzymatically active unit.

[0007] B and T-lymphocytes depend on the de novo, rather than salvagepathway, to generate sufficient levels of nucleotides necessary toinitiate a proliferative response to mitogen or antigen. Due to the Band T cell's unique reliance on the de novo pathway, IMPDH is anattractive target for selectively inhibiting the immune system withoutalso inhibiting the proliferation of other cells.

[0008] Immunosuppression has been achieved by inhibiting a variety ofenzymes. Examples include: phosphatase calcineurin (inhibited bycyclosporin and FK-506); dihydroorotate dehydrogenase (DHODase), anenzyme involved in the biosynthesis of pyrimidines (inhibited byleflunomide and brequinar); the kinase FRAP (inhibited by rapamycin);and the heat shock protein hsp70 (inhibited by deoxyspergualin).

[0009] Inhibitors of IMPDH have also been described in the art. WO97/40028 and U.S. Pat. No. 5,807,876 describe a class of ureaderivatives that possess a common urea backbone. WO 98/40381 describes aseries of heterocyclic substituted anilines as inhibitors of IMPDH.

[0010] U.S. Pat. Nos. 5,380,879 and 5,444,072 and PCT publications WO94/01105 and WO 94/12184 describe mycophenolic acid (“MPA”) and some ofits derivatives as potent, uncompetitive, reversible inhibitors of humanIMPDH type I and type II. MPA has been demonstrated to block theresponse of B and T-cells to mitogen or antigen. Immunosuppressants,such as MPA and derivatives of MPA, are useful drugs in the treatment oftransplant rejection and autoimmune disorders, psoriasis, inflammatorydiseases, including, rheumatoid arthritis, tumors and for the treatmentof allograft rejection. These are described in U.S. Pat. Nos. 4,686,234,4,725,622, 4,727,069, 4,753,935, 4,786,637, 4,808,592, 4,861,776,4,868,153, 4,948,793, 4,952,579, 4,959,387, 4,992,467, and 5,247,083.

[0011] The combination of agents for prevention and/or treatment ofIMPDH-associated disorders, especially allograft rejection, has beeninvestigated. In one study, it was observed that cyclic AMP agonists,such as Rolipram (Schering AG), a Type 4 Phosphodiesterase Inhibitor(PDE4) and immunomodulator, synergized with IMPDH inhibitor MPA by acAMP- and IMPDH-dependent dependent mechanism. (P. A. Canelos, L. M.Lichtenstein, S. K. Huang, D. M. Essayan, J. Allergy and ClinicalImmunology, 107:593 (2001)). The chemical structure of Rolipram is[4-[3-(cyclopentyloxy)-4-methoxy-phenyl]-2-pyrrolidinone]. Theinvestigators found that cyclic AMP agonists, such as the PDE4 inhibitorRolipram (Rol), markedly downregulated antigen-specific T lymphocyteresponses through their effects on a variety of signaling pathways. Inthe study, the potential for a very low concentration of Rol (10⁻⁷ M,approximate IC₁₀) to synergize with a variety of immunosuppressiveagents used for the prevention and/or treatment of allograft rejectionwas defined. While little or no synergistic effect on inhibition ofantigen-induced proliferation (assessed by ³H Thymidine incorporation)could be demonstrated with calcineurin antagonists (cyclosporine andtacrolimus), sirolimus, or corticosteroids, a marked synergistic effectwas demonstrated with MPA, the active metabolite of mycophenolatemofetil (CellCept, Roche). This effect was statistically significantover 4 orders of magnitude (10⁻⁶ to 10⁻⁹ M). This synergism wasrecapitulated with dibuteryl-cAMP (2×10⁻⁶ M, approximate IC₁₀) andinhibited with the use of H-9, suggesting a mechanism involving bothcAMP and protein kinase A.

[0012] Since MPA is a selective, uncompetitive, and reversible inhibitorof IMPDH, a key enzyme in the purine salvage pathway, the potential forcAMP-mediated cross-talk at this locus was further investigated. It wasfound that gene expression for IMPDH types I and II (assessed by RT-PCR)remained unaffected by the administration of rolipram, MPA, or both atlow and high concentrations. However, functional reversal of thesynergistic effect was demonstrated with the use of deoxyguanosine, aspecific antagonist of MPA on IMPDH (% inhibition of proliferation 81±16vs. 35±12, p<0.05). Finally, despite a marked synergistic effect oninhibition of proliferation, no significant downregulation in thegeneration of proinflammatory cytokines (IL-2, IL-4, and IFN, eachassessed by RT-PCR), could be detected with the administration of Rol10⁻⁷ M, MPA 10⁻⁸ M, or the combination. It was concluded that Roldemonstrates marked synergy with MPA by a cAMP- and IMPDH-dependentmechanism. The utility of this combination of agents for the inductionof T cell tolerance was suggested by the specificity of the observedeffect for proliferation, without the abrogation of cytokine generationand early signaling processes.

[0013] Tiazofurin, ribavirin and mizoribine also inhibit IMPDH. Thesenucleoside analogs are competitive inhibitors of IMPDH; however, theseagents inhibit other NAD dependent enzymes. This low level ofselectivity for IMPDH limits the therapeutic application of tiazofurin,ribavirin and mizoribine. Thus, new agents which have improvedselectivity for IMPDH would represent a significant improvement over thenucleoside analogs.

[0014] Mycophenolate mofetil, sold under the trade name CELLCEPT, is aprodrug which liberates MPA in vivo. It is approved for use inpreventing acute renal allograft rejection following kidneytransplantation. The side effect profile limits the therapeuticpotential of this drug. MPA is rapidly metabolized to the inactiveglucuronide in vivo. In humans, the blood levels of glucuronide exceedthat of MPA. The glucuronide undergoes enterohepatic recycling causingaccumulation of MPA in the bile and subsequently in the gastrointestinaltract. This together with the production of the inactive glucuronideeffectively lowers the drug's in vivo potency, while increasing itsundesirable gastrointestinal side effects.

[0015] Unlike type I, type II mRNA is preferentially upregulated inhuman leukemic cell lines K562 and HL-60. Weber, J. Biol. Chem. 266:506-509 (1991). In addition, cells from human ovarian tumors andleukemic cells from patients with chronic granulocytic, lymphocytic andacute myeloid leukemias also display an up regulation type II mRNA. Thisdisproportionate increase in IMPDH activity in malignant cells may beaddressed through the use of an appropriate IMPDH inhibitor. IMPDH hasalso been shown to play a role in the proliferation of smooth musclecells, indicating that inhibitors of IMPDH may be useful in preventingrestenosis or other hyperproliferative vascular diseases.

[0016] IMPDH has been shown to play a role in viral replication in someviral cell lines. Carr, J. Biol. Chem. 268:27286-27290 (1993). The IMPDHinhibitor VX-497, is currently being evaluated for the treatment ofhepatitis C virus in humans. Ribavirin has also been used in thetreatment of hepatitis C and B viruses and when used in combination withinterferon an enhancement in activity was observed. The IMPDH inhibitorribavirin is limited by its lack of a sustained response in monotherapyand broad cellular toxicity.

[0017] There remains a need for potent selective inhibitors of IMPDHwith improved pharmacological properties, physical properties and fewerside effects. Such inhibitors would have therapeutic potential asimmunosuppressants, anti-cancer agents, anti-vascular hyperproliferativeagents, antiinflammatory agents, antifungal agents, antipsoriatic andanti-viral agents. The compounds of the present invention are effectiveinhibitors of IMPDH.

SUMMARY OF THE INVENTION

[0018] It is an object of the present invention to provide heterocycliccompounds of the following formula (I), their enantiomers,diastereomers, tautomers and pharmaceutically acceptable salts, prodrugsand solvates thereof, for use as IMPDH inhibitors:

[0019] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0020] X¹ is C═O, —S(O)—, or —S()₂—;

[0021] X² is CR³ or N;

[0022] X³ is —NH—, —O—, or —S—;

[0023] X⁴ is CR⁴ or N;

[0024] X⁵ is CR⁵ or N;

[0025] X⁶ is CR⁶ or N;

[0026] R¹ is alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, NR⁸R⁹, SR²⁰, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;

[0027] R² is halogen, cyano, nitro, hydroxy, oxo (double bond is nolonger present between CR² and X⁶), SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁸R⁹, CO₂R⁷,C(O)NR⁸R⁹, or heteroaryl;

[0028] R³ is hydrogen, hydroxy, halogen, cyano, CO₂R⁷, NR⁸R⁹, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl or heteroaryl;

[0029] R⁴, R⁵, and R⁶ are independently selected from the groupconsisting of hydrogen, halogen, nitro, cyano, O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷,SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, C(O)alkyl, C(O)substitutedalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyland substituted alkynyl;

[0030] R⁷, R¹⁰, and R¹¹, are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,cycloalkyl, substituted cycloalkyl, C(O)alkyl, C(O)substituted alkyl,C(O)cycloalkyl, C(O) substituted cycloalkyl, C(O)aryl, C(O)substitutedaryl, C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)heterocycloalkyl,C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;

[0031] R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, alkynyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl,C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl,C(O)Osubstituted alkyl, C(O)heterocycloalkyl, C(O)heeroaryl, aryl,substituted aryl, heterocycloalkyl, and heteroaryl or R⁸ and R⁹ takentogether with the nitrogen atom to which they are attached complete aheterocycloalkyl or heteroaryl ring;

[0032] R²⁰ is alkyl, substituted alkyl, cycloalkyl, aryl, substitutedaryl, heteroaryl or heterocycloalkyl;

[0033] R³ and R¹ may be taken together with the carbon atoms to whichthey are attached to form a monocyclic or substituted monocyclic ringsystem of 5 or 6 carbon atoms; and

[0034] R⁴ and R⁵ may be joined together by the chain —O—CH₂—O— or—O—CH₂—CH₂—O—.

[0035] It is another object of the present invention to providepharmaceutical compositions containing the IMPDH inhibitor compounds ofthe invention.

[0036] It is yet another object of the present invention to providemethods for treating inosine monophosphate dehydrogenase associateddisorders using the IMPDH inhibitor compounds of the invention. It is afurther object of the present invention to provide methods for treatingtreating inosine monophosphate dehydrogenase associated disorders andpreventing or treating allograft rejection using the IMPDH inhibitorcompounds of the invention and phosphodiesterase Type 4 inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

[0037] [1] Thus in a first embodiment, the present invention provides amethod of treating inosine monophosphate dehydrogenase associateddisorders comprising: administering a therapeutically effective amountof a compound of formula (I)

[0038] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0039] X¹ is C═O, —S(O)—, or —S(O)₂—;

[0040] X² is CR³ or N;

[0041] X³ is —NH—, —O—, or —S—;

[0042] X⁴ is CR⁴ or N;

[0043] X⁵ is CR⁵ or N;

[0044] X⁶ is CR⁶ or N;

[0045] R¹ is alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, NR⁸R⁹, SR²⁰, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;

[0046] R² is halogen, cyano, nitro, hydroxy, oxo (double bond is nolonger present between CR² and X⁶), SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁸R⁹, CO₂R⁷,C(O)NR⁸R⁹, or heteroaryl;

[0047] R³ is hydrogen, hydroxy, halogen, cyano, CO₂R⁷, NR⁸R⁹, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl or heteroaryl;

[0048] R⁴, R⁵, and R⁶ are independently selected from the groupconsisting of hydrogen, halogen, nitro, cyano, O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷,SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, CO₂R⁷ ₁ C(O)NR⁸R⁹, C(O)alkyl, C(O)substitutedalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyland substituted alkynyl;

[0049] R⁷, R¹⁰, and R¹¹, are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,cycloalkyl, substituted cycloalkyl, C(O)alkyl, C(O)substituted alkyl,C(O)cycloalkyl, C(O) substituted cycloalkyl, C(O)aryl, C(O)substitutedaryl, C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)heterocycloalkyl,C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;

[0050] R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, alkynyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl,C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl,C(O)Osubstituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl,substituted aryl, heterocycloalkyl, and heteroaryl or R⁸ and R⁹ takentogether with the nitrogen atom to which they are attached complete aheterocycloalkyl or heteroaryl ring;

[0051] R²⁰ is alkyl, substituted alkyl, cycloalkyl, aryl, substitutedaryl, heteroaryl or heterocycloalkyl;

[0052] R³ and R¹ may be taken together with the carbon atoms to whichthey are attached to form a monocyclic or substituted monocyclic ringsystem of 5 or 6 carbon atoms; and

[0053] R⁴ and R⁵ may be joined together by the chain —O—CH₂—O— or—O—CH₂—CH₂—O—.

[0054] [2] In a preferred embodiment, the present invention provides amethod of treating inosine monophosphate dehydrogenase associateddisorders comprising: administering a therapeutically effective amountof a compound of formula (II)

[0055] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0056] R² is a monocyclic substituted or unsubstituted heteroaryl group.

[0057] [3] In another preferred embodiment, the present inventionprovides a method of treating inosine monophosphate dehydrogenaseassociated disorders comprising: administering a therapeuticallyeffective amount of a compound of formula (III)

[0058] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0059] R² is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, orsubstituted 5-oxazolyl;

[0060] R³ is hydrogen, hydroxy, NR⁸R⁹, alkyl of 1 to 4 carbons, alkenylof 2 to 4 carbons, alkynyl of 2 to 4 carbons, substituted alkyl of 1 to4 carbons, phenyl, substituted phenyl, cycloalkyl of 5 to 7 carbons,substituted cycloalkyl of 5 to 7 carbons, monocyclic heterocycloalkyland monocyclic heteroaryl;

[0061] R⁴ is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons,cyano, CF₃, OCF₃, OCH₃, SCH₃, S(O)CH₃, or S(O)₂CH₃;

[0062] R⁵ is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons,cyano, vinyl, CF₃, CF₂CF₃, CH═CF₂, OCH₃, OCF₃, OCHF₂, SCH₃, S(O)CH₃, orS(O)₂CH₃; and

[0063] R⁶ is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons,cyano, CF₃, OCH₃, OCF₃, SCH₃, S(O)CH₃, and S(O)₂CH₃.

[0064] [4] In another preferred embodiment, the present inventionprovides a method of treating inosine monophosphate dehydrogenaseassociated disorders comprising: administering a therapeuticallyeffective amount of a compound including isomers, enantiomers,diastereomers, tautomers, pharmaceutically acceptable salts, prodrugsand solvates wherein:

[0065] R² is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, substituted5-oxazolyl or heteroaryl;

[0066] R³ is hydrogen, hydroxy, halogen, methyl or NR⁸R⁹;

[0067] R⁴ is hydrogen;

[0068] R⁵ is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMe orOCF₃; and

[0069] R⁶ is hydrogen.

[0070] [5] In another preferred embodiment, the present inventionprovides a method of treating inosine monophosphate dehydrogenaseassociated disorders comprising: administering a therapeuticallyeffective amount of a compound including isomers, enantiomers,diastereomers, tautomers, pharmaceutically acceptable salts, prodrugsand solvates wherein:

[0071] R² is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl orsubstituted 5-oxazolyl;

[0072] R³ is hydrogen, hydroxy, halogen or methyl;

[0073] R⁴ is hydrogen;

[0074] R⁵ is halogen, methyl or OMe; and

[0075] R⁶ is hydrogen.

[0076] [6] In an even more preferred embodiment, the present inventionprovides a method of treating inosine monophosphate dehydrogenaseassociated disorders comprising: administering a therapeuticallyeffective amount of a phosphodiesterase Type 4 inhibitor and a compoundof formula (X):

[0077] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0078] X¹ is C═O, —S(O)—, or —S(O)₂—;

[0079] X² is CR³ or N;

[0080] X³ is —NH—, —O—, or —S—;

[0081] X⁴ is CR⁴ or N;

[0082] X⁵ is CR⁵ or N;

[0083] X⁶ is CR⁶ or N;

[0084] R¹ is alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, NR⁸R⁹, SR²⁰, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;

[0085] R² is halogen, cyano, nitro, hydroxy, oxo (double bond is nolonger present between CR² and X⁶), SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁸R⁹, CO₂R⁷,C(O)NR⁸R⁹, or heteroaryl;

[0086] R³ is hydrogen, hydroxy, halogen, cyano, CO₂R⁷, NR⁸R⁹ ₁ alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl or heteroaryl;

[0087] R⁴, R⁵, and R⁶ are independently selected from the groupconsisting of hydrogen, halogen, nitro, cyano, O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷,SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, C(O)alkyl, C(O)substitutedalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyland substituted alkynyl;

[0088] R⁷, R¹⁰, and R¹¹, are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,cycloalkyl, substituted cycloalkyl, C(O)alkyl, C(O)substituted alkyl,C(O)cycloalkyl, C(O) substituted cycloalkyl, C(O)aryl, C(O)substitutedaryl, C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)heterocycloalkyl,C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;

[0089] R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, alkynyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl,C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl,C(O)Osubstituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl,substituted aryl, heterocycloalkyl, and heteroaryl or R⁸ and R⁹ takentogether with the nitrogen atom to which they are attached complete aheterocycloalkyl or heteroaryl ring;

[0090] R²⁰ is alkyl, substituted alkyl, cycloalkyl, aryl, substitutedaryl, heteroaryl or heterocycloalkyl;

[0091] R³ and R¹ may be taken together with the carbon atoms to whichthey are attached to form a monocyclic or substituted monocyclic ringsystem of 5 or 6 carbon atoms; and

[0092] R⁴ and R⁵ may be joined together by the chain —O—CH₂—O— or—O—CH₂—CH₂—O—.

[0093] [7] In another even more preferred embodiment, the presentinvention provides a method for the treatment or prevention of allograftrejection comprising: administering a therapeutically effective amountof a phosphodiesterase Type 4 inhibitor and a compound of formula (X):

[0094] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0095] X¹ is C═O, —S(O)—, or —S(O)₂—;

[0096] X² is CR³ or N;

[0097] X³ is —NH—, —O—, or —S—;

[0098] X⁴ is CR or N;

[0099] X⁵ is CR⁵ or N;

[0100] X⁶ is CR⁶ or N;

[0101] R¹ is alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, NR⁸R⁹, SR²⁰, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl;

[0102] R² is halogen, cyano, nitro, hydroxy, oxo (double bond is nolonger present between CR² and X⁶), SR⁷, S(O)R⁷, SO₂R , SO₂NR⁸R⁹, CO₂R⁷,C(O)NR⁸R⁹, or heteroaryl;

[0103] R³ is hydrogen, hydroxy, halogen, cyano, CO₂R⁷, NR⁸R⁹, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl or heteroaryl;

[0104] R⁴, R⁵, and R⁶ are independently selected from the groupconsisting of hydrogen, halogen, nitro, cyano, O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷,SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, C(O)alkyl, C(O)substitutedalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyland substituted alkynyl;

[0105] R⁷, R¹⁰, and R¹¹, are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,cycloalkyl, substituted cycloalkyl, C(O)alkyl, C(O)substituted alkyl,C(O)cycloalkyl, C(O) substituted cycloalkyl, C(O)aryl, C(O)substitutedaryl, C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)heterocycloalkyl,C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;

[0106] R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, alkynyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl,C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl,C(O)Osubstituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl,substituted aryl, heterocycloalkyl, and heteroaryl or R⁸ and R⁹ takentogether with the nitrogen atom to which they are attached complete aheterocycloalkyl or heteroaryl ring;

[0107] R²⁰ is alkyl, substituted alkyl, cycloalkyl, aryl, substitutedaryl, heteroaryl or heterocycloalkyl;

[0108] R³ and R¹ may be taken together with the carbon atoms to whichthey are attached to form a monocyclic or substituted monocyclic ringsystem of 5 or 6 carbon atoms; and

[0109] R⁴ and R⁵ may be joined together by the chain —O—CH₂—O— or—O—CH₂—CH₂—O—.

[0110] [8] In another even more preferred embodiment, thephosphodiesterase Type 4 inhibitor is Rolipram.

[0111] [9] In another even more preferred embodiment, thephosphodiesterase Type 4 inhibitor is[4-[3-(cyclopentyloxy)-4-methoxy-phenyl]-2-pyrrolidinone].

[0112] [10] In a second embodiment, the present invention provides anovel compound, comprising: a compound of formula (I)

[0113] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0114] X¹ is C═O, —S(O)—, or —S(O)₂—;

[0115] X² is CR³ or N;

[0116] X³ is —NH—, —O—, or —S—;

[0117] X⁴ is CR⁴ or N;

[0118] X⁵ is CR⁵ or N;

[0119] X⁶ is CR⁶ or N;

[0120] R¹ is alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heterocycloalkyl, or heteroaryl;

[0121] R² is cyano, hydroxy, oxo (double bond is no longer presentbetween CR² and X⁶), SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, orheteroaryl;

[0122] R³ is hydrogen, hydroxy, halogen, cyano, CO₂R⁷, NR⁸R⁹, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl or heteroaryl;

[0123] R⁴, R⁵, and R⁶ are independently selected from the groupconsisting of hydrogen, halogen, nitro, cyano, O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷,SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, C(O)alkyl, C(O)substitutedalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyland substituted alkynyl;

[0124] R⁷, R¹⁰, and R¹¹, are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,cycloalkyl, substituted cycloalkyl, C(O)alkyl, C(O)substituted alkyl,C(O)cycloalkyl, C(O) substituted cycloalkyl, C(O)aryl, C(O)substitutedaryl, C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)heterocycloalkyl,C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;

[0125] R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, alkynyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl,C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl,C(O)Osubstituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl,substituted aryl, heterocycloalkyl, and heteroaryl or R⁸ and R⁹ takentogether with the nitrogen atom to which they are attached complete aheterocycloalkyl or heteroaryl ring;

[0126] R³ and R¹ may be taken together with the carbon atoms to whichthey are attached to form a monocyclic or substituted monocyclic ringsystem of 5 or 6 carbon atoms; and

[0127] R⁴ and R⁵ may be joined together by the chain —O—CH₂—O— or—O—CH₂—CH₂—O—;

[0128] with the following provisos:

[0129] (a) when X¹ is C═O, X² is CR³, X³ is NH, X⁴ is CR⁴, X⁵ is CR⁵, X⁶is CR⁶, R¹ is substituted or meta unsubstituted phenyl, R³ is H, R⁴ isH, R⁵ is H and R⁶ is H, then R² is not PhCONH,

[0130] (b) when X¹ is C═O, X² is CR³, X³ is NH, X⁴ is CR⁴, X⁵ is CR⁵, X⁶is CR⁶, R¹ is phenyl substituted with H, F, Cl, Br, I, CH₃, CF₃, OH,OCH₃, OCF₃, OCH₂CH₃, NH₂, NHCH₃, N(CH₃)₂, O-benzyl, —C(═O)—R₀, or—C(═O)—OR₀ and R₀ is a lower alkyl group, R³ is H, R⁴ is H, R⁵ is H andR⁶ is H, then R² is not

[0131]  where Y is CH₂, O or S, m and n are each greater than 1, and thesum of m and n is between 3 and 6; and

[0132] (c) when R² is heteroaryl, at least one of the heteroatoms mustbe O;

[0133] [11] In a preferred embodiment, the present invention provides acompound of formula (II)

[0134] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0135] R² is a monocyclic substituted or unsubstituted heteroaryl group.

[0136] [12] In a more preferred embodiment, the present inventionprovides a compound of formula (III)

[0137] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein:

[0138] R² is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, orsubstituted 5-oxazolyl;

[0139] R³ is hydrogen, hydroxy, NR⁸R⁹, alkyl of 1 to 4 carbons, alkenylof 2 to 4 carbons, alkynyl of 2 to 4 carbons, substituted alkyl of 1 to4 carbons, phenyl, substituted phenyl, cycloalkyl of 5 to 7 carbons,substituted cycloalkyl of 5 to 7 carbons, monocyclic heterocycloalkyland monocyclic heteroaryl;

[0140] R⁴ is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons,cyano, CF₃, OCF₃, OCH₃, SCH₃, S(O)CH₃, or S(O)₂CH₃;

[0141] R⁵ is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons,cyano, vinyl, CF₃, CF₂CF₃, CH═CF₂, OCH₃, OCF₃, OCHF₂, SCH₃, S(O)CH₃, orS(O)₂CH₃; and

[0142] R⁶ is hydrogen, halogen, nitro, hydroxy, alkyl of 1 to 4 carbons,cyano, CF₃, OCH₃, OCF₃, SCH₃, S(O)CH₃, and S(O)₂CH₃.

[0143] [13] In an even more preferred embodiment, the present inventionprovides a compound including isomers, enantiomers, diastereomers,tautomers, pharmaceutically acceptable salts, prodrugs and solvateswherein:

[0144] R² is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, substituted5-oxazolyl or heteroaryl;

[0145] R³ is hydrogen, hydroxy, halogen, methyl or NR⁸R⁹;

[0146] R⁴ is hydrogen;

[0147] R⁵ is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMe orOCF₃; and

[0148] R⁶ is hydrogen.

[0149] [14] In another even more preferred embodiment, the presentinvention provides a compound including isomers, enantiomers,diastereomers, tautomers, pharmaceutically acceptable salts, prodrugsand solvates wherein:

[0150] R² is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl orsubstituted 5-oxazolyl;

[0151] R³ is hydrogen, hydroxy, halogen or methyl;

[0152] R⁴ is hydrogen;

[0153] R⁵ is halogen, methyl or OMe; and

[0154] R⁶ is hydrogen.

[0155] [15] In another even more preferred embodiment, the presentinvention provides a compound of formula (V)

[0156] including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates selected from:

[0157] a compound of formula (V) wherein:

[0158] R¹ is

[0159] and R³ is hydrogen;

[0160] a compound of formula (V) wherein:

[0161] R³ is

[0162] and R³ is hydrogen;

[0163] a compound of formula (V) wherein:

[0164] R³ is

[0165] and R³ is hydrogen;

[0166] a compound of formula (V) wherein:

[0167] R¹ is CH₃ and R3 is hydrogen;

[0168] a compound of formula (V) wherein:

[0169] R¹ is

[0170] and R³ is CH₃;

[0171] a compound of formula (V) wherein:

[0172] R¹ is

[0173] and R³ is hydrogen;

[0174] a compound of formula (V) wherein:

[0175] R¹ is

[0176] and R³ is hydrogen;

[0177] a compound of formula (V) wherein:

[0178] R¹ is

[0179] and R³ is hydrogen;

[0180] a compound of formula (V) wherein:

[0181] R¹ is

[0182] and R³ is hydrogen;

[0183] a compound of formula (V) wherein: R¹ is

[0184] and R³ is hydrogen;

[0185] a compound of formula (V) wherein: R¹ is

[0186] and R³ is hydrogen;

[0187] a compound of formula (V) wherein:

[0188] R¹ is

[0189] and R³ is hydrogen;

[0190] a compound of formula (V) wherein:

[0191] R¹ is

[0192] and R³ is hydrogen;

[0193] a compound of formula (V) wherein:

[0194] R¹ is

[0195] and R³ is hydrogen;

[0196] a compound of formula (V) wherein:

[0197] R¹ is

[0198] and R³ is hydrogen;

[0199] a compound of formula (V) wherein:

[0200] R¹ is

[0201] and R³ is hydrogen;

[0202] a compound of formula (V) wherein:

[0203] R¹ is

[0204] and R³ is hydrogen;

[0205] a compound of formula (V) wherein:

[0206] R¹ is

[0207] and R³ is hydrogen;

[0208] a compound of formula (V) wherein:

[0209] R¹ is

[0210] and R³ is hydrogen;

[0211] a compound of formula (V) wherein:

[0212] R¹ is

[0213] and R³ is hydrogen;

[0214] a compound of formula (V) wherein:

[0215] R¹ is

[0216] and R³ is hydrogen;

[0217] a compound of formula (V) wherein:

[0218] R¹ is

[0219] and R³ is hydrogen;

[0220] a compound of formula (V) wherein:

[0221] R¹ is

[0222] and R³ is hydrogen;

[0223] a compound of formula (V) wherein:

[0224] R¹ is

[0225] and R³ is hydrogen;

[0226] a compound of formula (V) wherein:

[0227] R¹ is

[0228] and R³ is hydrogen;

[0229] a compound of formula (V) wherein:

[0230] R¹ is

[0231] and R³ is hydrogen;

[0232] a compound of formula (V) wherein:

[0233] R¹ is

[0234] and R³ is Br;

[0235] a compound of formula (V) wherein:

[0236] and R³ is hydrogen;

[0237] a compound of formula (V) wherein:

[0238] R¹ is

[0239] and R³ is hydrogen;

[0240] a compound of formula (V) wherein:

[0241] R¹ is

[0242] and R³ is hydrogen;

[0243] a compound of formula (V) wherein:

[0244] R¹ is

[0245] and R³ is hydrogen;

[0246] a compound of formula (V) wherein:

[0247] R¹ is

[0248] and R³ is hydrogen;

[0249] a compound of formula (V) wherein:

[0250] R¹ is

[0251] and R³ is hydrogen;

[0252] a compound of formula (V) wherein:

[0253] R¹ is

[0254] and R³ is hydrogen;

[0255] a compound of formula (V) wherein:

[0256] R¹ is

[0257] and R³ is hydrogen;

[0258] a compound of formula (V) wherein:

[0259] R¹ is

[0260] and R³ is hydrogen;

[0261] a compound of formula (V) wherein:

[0262] R¹ is

[0263] and R³ is hydrogen;

[0264] a compound of formula (V) wherein:

[0265] R¹ is

[0266] and R³ is hydrogen;

[0267] a compound of formula (V) wherein:

[0268] R¹ is

[0269] and R³ is hydrogen;

[0270] a compound of formula (V) wherein:

[0271] R¹ is

[0272] and R³ is hydrogen;

[0273] a compound of formula (V) wherein:

[0274] R¹ is

[0275] and R³ is hydrogen;

[0276] a compound of formula (V) wherein:

[0277] R¹ is

[0278] and R³ is hydrogen;

[0279] a compound of formula (V) wherein:

[0280] R¹ is

[0281] and R³ is hydrogen;

[0282] a compound of formula (V) wherein:

[0283] R¹ is

[0284] and R³ is hydrogen;

[0285] a compound of formula (V) wherein:

[0286] R¹ is

[0287] and R³ is hydrogen;

[0288] a compound of formula (V) wherein:

[0289] R¹ is

[0290] and R³ is hydrogen;

[0291] a compound of formula (V) wherein:

[0292] R¹ is

[0293] and R³ is hydrogen;

[0294] a compound of formula (V) wherein:

[0295] R¹ is

[0296] and R³is hydrogen;

[0297] a compound of formula (V) wherein:

[0298] R¹ is

[0299] and R³is hydrogen;

[0300] a compound of formula (V) wherein:

[0301] R¹ is

[0302] and R³ is hydrogen;

[0303] a compound of formula (V) wherein:

[0304] R¹ is

[0305] and R³ is hydrogen;

[0306] a compound of formula (V) wherein:

[0307] R¹ is

[0308] and R³ is hydrogen;

[0309] a compound of formula (V) wherein:

[0310] R¹ is

[0311] and R³ is hydrogen;

[0312] a compound of formula (V) wherein:

[0313] R¹ is

[0314] and R³ is hydrogen;

[0315] a compound of formula (V) wherein:

[0316] R¹ is

[0317] and R³ is hydrogen;

[0318] a compound of formula (V) wherein:

[0319] R¹ is

[0320] and R³ is hydrogen;

[0321] a compound of formula (V) wherein:

[0322] R¹ is

[0323] and R³ is hydrogen;

[0324] a compound of formula (V) wherein:

[0325] R¹ is

[0326] and R³ is hydrogen;

[0327] a compound of formula (V) wherein:

[0328] R¹ is

[0329] and R³ is hydrogen;

[0330] a compound of formula (V) wherein:

[0331] R¹ is

[0332] and R³ is hydrogen;

[0333] a compound of formula (V) wherein:

[0334] R¹ is

[0335] and R³ is hydrogen;

[0336] a compound of formula (V) wherein:

[0337] R¹ is

[0338] and R³ is hydrogen;

[0339] a compound of formula (V) wherein:

[0340] R¹ is

[0341] and R³ is hydrogen;

[0342] a compound of formula (V) wherein:

[0343] R¹ is

[0344] and R³ is hydrogen;

[0345] a compound of formula (V) wherein:

[0346] R¹ is

[0347] and R³ is hydrogen;

[0348] a compound of formula (V) wherein:

[0349] R¹ is

[0350] and R³ is hydrogen;

[0351] a compound of formula (V) wherein:

[0352] R¹ is

[0353] and R³ is hydrogen;

[0354] a compound of formula (V) wherein:

[0355] R¹ is

[0356] and R³ is hydrogen;

[0357] a compound of formula (V) wherein:

[0358] R¹ is

[0359] and R³ is hydrogen;

[0360] a compound of formula (V) wherein:

[0361] R¹ is

[0362] and R³ is hydrogen;

[0363] a compound of formula (V) wherein:

[0364] R¹ is

[0365] and R³ is hydrogen;

[0366] a compound of formula (V) wherein:

[0367] R¹ is

[0368] and R³ is hydrogen;

[0369] a compound of formula (V) wherein:

[0370] R¹ is

[0371] and R³ is hydrogen;

[0372] a compound of formula (V) wherein:

[0373] R¹ is

[0374] and R³ is hydrogen;

[0375] a compound of formula (V) wherein:

[0376] R¹ is

[0377] and R³ is hydrogen;

[0378] a compound of formula (V) wherein:

[0379] R¹ is

[0380] and R³ is hydrogen;

[0381] a compound of formula (V) wherein:

[0382] R¹ is

[0383] and R³ is hydrogen;

[0384] a compound of formula (V) wherein:

[0385] R¹ is

[0386] and R³ is hydrogen;

[0387] a compound of formula (V) wherein:

[0388] R¹ is

[0389] and R³ is hydrogen;

[0390] a compound of formula (V) wherein:

[0391] R¹ is

[0392] and R³ is hydrogen;

[0393] a compound of formula (V) wherein:

[0394] R¹ is

[0395] and R³ is hydrogen;

[0396] a compound of formula (V) wherein:

[0397] R¹ is

[0398] and R³ is hydrogen;

[0399] a compound of formula (V) wherein:

[0400] R¹ is

[0401] and R³ is hydrogen;

[0402] a compound of formula (V) wherein:

[0403] R¹ is

[0404] and R³ is hydrogen;

[0405] a compound of formula (V) wherein:

[0406] R¹ is

[0407] and R³ is hydrogen;

[0408] a compound of formula (V) wherein:

[0409] R¹ is

[0410] and R³ is hydrogen;

[0411] a compound of formula (V) wherein:

[0412] R¹ is

[0413] and R³ is hydrogen;

[0414] a compound of formula (V) wherein:

[0415] R¹ is

[0416] and R³ is hydrogen;

[0417] a compound of formula (V) wherein:

[0418] R¹ is

[0419] and R³ is hydrogen;

[0420] a compound of formula (V) wherein:

[0421] R¹ is

[0422] and R³ is hydrogen;

[0423] a compound of formula (V) wherein:

[0424] R¹ is

[0425] and R³ is hydrogen;

[0426] and a compound of formula (V) wherein:

[0427] R¹ is

[0428] and R³ is hydrogen.

[0429] [16] In another even more preferred embodiment, the presentinvention provides a compound including isomers, enantiomers,diastereomers, tautomers, pharmaceutically acceptable salts, prodrugsand solvates thereof selected from:

[0430] [17] In a third preferred embodiment, the present inventionprovides a pharmaceutical composition comprising: a compound of theinvention and a pharmaceutically acceptable carrier.

[0431] [18] In another preferred embodiment, the present inventionprovides a method of treating inosine monophosphate dehydrogenaseassociated disorders comprising: administering an effective amount ofthe pharmaceutical composition of the invention.

[0432] [19] In another preferred embodiment, the present inventionprovides a method of treating inosine monophosphate dehydrogenaseassociated disorders comprising: administering an effective amount ofthe pharmaceutical composition of the invention and another agent knownto be useful in treatment of such disorders.

[0433] [20] In another preferred embodiment, the present inventionprovides a method of treating inosine monophosphate dehydrogenaseassociated disorders comprising: administering a therapeuticallyeffective amount of the pharmaceutical composition of the invention anda phosphodiesterase Type 4 inhibitor.

[0434] [21] In a another preferred embodiment, the present inventionprovides a method for the treatment or prevention of allograft rejectioncomprising: administering a therapeutically effective amount of thepharmaceutical composition of the invention and a phosphodiesterase Type4 inhibitor.

[0435] The following are definitions of the terms as used throughoutthis specification and claims. The initial definition provided for agroup or term herein applies to that group or term throughout thepresent specification, individually or as part of another group, unlessotherwise indicated.

[0436] The term “alkyl” refers to straight or branched chain hydrocarbongroups having 1 to 12 carbons atoms, preferably 1 to 8 carbon atoms, andmost preferably 1 to 4 carbon atoms.

[0437] The term “substituted alkyl” refers to an alkyl group as definedabove having one, two, or three substituents selected from the groupconsisting of halo, cyano, O—R⁷, S—R⁷, NR⁸R⁹, nitro, cycloalkyl,substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl,heteroaryl, CO₂R⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, C(O)NR⁸R⁹, C(O)alkyl,and C(O)H.

[0438] The term “alkenyl” refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and one, two or threedouble bonds, preferably 2 to 6 carbon atoms and one double bond.

[0439] The term “substituted alkenyl” refers to an alkenyl group asdefined above having one, two, or three substituents selected from thegroup consisting of halo, cyano, O—R⁷, S—R⁷, NR⁸R⁹, nitro, cycloalkyl,substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl,heteroaryl, CO₂R⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, C(O)NR⁸R⁹, C(O)alkyl,and C(O)H.

[0440] The term “alkynyl” refers to straight or branched chainhydrocarbon group having 2 to 12 carbon atoms and one, two or threetriple bonds, preferably 2 to 6 carbon atoms and one triple bond.

[0441] The term “substituted alkynyl” refers to an alkynyl group asdefined above having one, two or three substituents selected from thegroup consisting of halo, cyano, O—R⁷, S—R⁷, NR⁸R⁹, nitro, cycloalkyl,substituted cycloalkyl, oxo, aryl, substituted aryl, heterocycloalkyl,heteroaryl, CO₂R⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, C(O)NR⁸R⁹, C(O)alkyl,and C(O) H.

[0442] The term “halo” refers to chloro, bromo, fluoro, and iodo.

[0443] The term “cycloalkyl” refers to fully saturated and partiallyunsaturated monocyclic hydrocarbon rings of 3 to 9, preferably 3 to 7carbon atoms. Also included in this definition are bicyclic rings wherethe cycloalkyl ring as defined above has a fused aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or heteroaryl ringprovided that the point of attachment is in the cycloalkyl ring, i.e.

[0444] etc., as well as a cycloalkyl ring as defined above having a twoor three carbon bridge or a spirocycloalkyl in which a carbon atom ofthe cycloallkyl ring has a carbon atom in common with a secondcycloalkyl, substituted cycloalkyl, or heterocycloalkyl ring againprovided that the point of attachment is in the cycloalkyl ring, i.e.

[0445] etc,

[0446] The term “substituted cycloalkyl” refers to such cycloalkyl groupas defined above having one, two or three substituents selected from thegroup consisting of halogen, nitro, alkyl, substituted alkyl, alkenyl,cyano, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl, heteroaryl, oxo, OR⁷, CO₂R⁷, C(O)NR⁸R⁹, OC(O)R⁷,OC(O)OR⁷, OC(O)NR⁸R⁹, OCH₂CO₂R⁷, C(O)R⁷, NR⁸R⁹ NR¹⁰C(O)R⁷ NR¹⁰C(O)OR⁷,NR¹⁰C(O)C(O)OR⁷, NR¹⁰C(O)C(O)NR⁸R⁹, NR¹⁰C(O)C(O)alkyl, NR¹⁰C(NCN)OR⁷,NR¹⁰C(O)NR⁸R⁹, NR¹⁰C(NCN)NR⁸R⁹, NR¹⁰C(NR¹¹)NR⁸R⁹, NR¹⁰SO₂NR⁸R⁹,NR¹⁰SO₂R⁷, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, NHOR⁷, NR¹⁰NR⁸R⁹,N(COR⁷)OR¹⁰, N(CO₂R⁷)OR¹⁰, C(O)NR¹⁰(CR¹²R¹³)rR⁷, CO(CR¹² R¹³)pO(CR¹⁴R¹⁵)qCO₂R₇, CO(CR¹² R¹³)rOR⁷, CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qR⁷,CO(CR¹²R¹³)rNR⁸R⁹, OC(O)O(CR¹²R¹³)mNR⁸R⁹, OC(O)N(CR¹²R¹³)rR⁷,O(CR¹²R¹³)mNR⁸R⁹, NR¹⁰C(O)(CR¹²R¹³)rR⁷, NR¹⁰C(O)(CR¹²R¹³)rOR⁷,NR¹⁰C(═NC)(CR¹²R¹³)rR⁷, NR¹⁰CO(CR¹²R¹³)rNR⁸R⁹, NR(CR¹²R¹³)mOR⁷,NR¹⁰(CR¹²R¹³)rCO₂R₇, NR¹⁰(CR¹²R¹³)mNR⁸R⁹, NR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹⁵)qR⁷,CONR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹⁵)qR⁷, SO₂NR¹⁰(CR¹²R¹³)nCO(CR¹⁴R¹⁵)qR⁷, andSO₂NR¹⁰(CR¹²R¹³)mOR⁷.

[0447] The term “aryl” refers to the phenyl, 1-naphthyl, and 2-naphthyl,preferably phenyl, as well as an aryl ring having a fused cycloalkyl,substituted cycloalkyl, heterocycloalkyl, or heteroaryl ring providedthat the point of attachment is in the aryl ring, i.e.

[0448] The term “substituted aryl” refers to such aryl groups as definedabove having one, two, or three substituents selected from the groupconsisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl, heteroaryl, OR⁷, CO₂R⁷, C(O)NR⁸R⁹, OC(O)R⁷, OC(O)OR⁷,OC(O)NR⁸R⁹, OCH₂CO₂R⁷ ₁ C(O)R⁷, NR⁸R⁹, NR¹⁰C(O)R⁷, NR¹⁰C(O)OR⁷,NR¹⁰C(O)C(O)OR⁷, NR¹⁰C(O)C(O)NR⁸R⁹, NR¹⁰C(O)C(O)alkyl, NR¹⁰C(NCN)OR⁷,NR¹⁰C(O)NR⁸R⁹, NR¹⁰(NCN)NR⁸R⁹, NR¹⁰C(NR¹¹)NR⁸R⁹, NR¹⁰SO₂NR⁸R⁹,NR¹⁰SO₂R⁷, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, NHOR⁷, NR¹⁰NR⁸R⁹,N(COR⁷)OR¹⁰, N(CO₂R⁷)OR¹⁰, C(O)NR¹⁰(CR¹²R¹³)rR⁷,CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qCO₂R₇, CO(CR¹²R¹³)rOR⁷,CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qR⁷, CO(CR¹²R¹³)rNR⁸R⁹, OC(O)O(CR¹²R¹³)mNR⁸R⁹,OC(O)N(CR¹²R¹³)rR⁷, O(CR¹²R^(13/))mNR⁸R⁹, NR¹⁰C(O)(CR¹²R¹³)rR⁷,NR¹⁰C(O)(CR¹²R¹³)rOR⁷, NR¹⁰C(═NC)(CR¹²R¹³)rR⁷, NR¹⁰CO(CR¹²R¹³)rNR⁸R⁹,NR¹⁰(CR¹²R¹³)mOR⁷, NR¹⁰(CR¹²R¹³)rCO₂R₇, NR¹⁰(CR¹²R¹³)mNR⁸R⁹,NR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹⁵)qR⁷, CONR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹¹⁵) qR⁷,SO₂NR¹⁰(CR¹²R¹³)nCO(CR¹⁴R¹⁵)qR⁷, and SO₂NR¹⁰(CR¹²R¹³)mOR⁷ as well aspentafluorophenyl.

[0449] The term “substituted monocyclic ring system of 5 or 6 carbonatoms” refers to one, two or three substituents selected from the groupconsisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano,oxo, OR⁷, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl, heteroaryl, CO₂R⁷, C(O)NR⁸R⁹, OC(O)R⁷, OC(O)OR⁷,OC(O)NR⁸R⁹, OCH₂CO₂R⁷, C(O)R⁷, NR⁸R⁹, NR¹⁰C(O)C(O)alkyl, NR¹⁰C(NCN)OR⁷,NR¹⁰C(O)NR⁸R⁹, NR¹⁰C(NCN)NR⁸R⁹, NR¹⁰C(NR¹¹)NR⁸R⁹, NR¹⁰SO₂NR⁸R⁹, NR¹⁰SO₂RS(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, NHOR⁷, NR¹⁰NR⁸R⁹, N(COR⁷)OR¹⁰,N(CO₂R⁷)OR¹⁰, C(O)NR¹⁰(CR¹²R¹³)rR⁷, CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qCO₂R₇,CO(CR¹²R¹³)rOR⁷, CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qR⁷, CO(CR¹²R¹³)rNR⁸R⁹,OC(O)O(CR¹²R¹³)mNR⁸R⁹, OC(O)N(CR¹²R¹³)rR⁷, O(CR¹²R¹³)mNR⁸R⁹,NR¹⁰C(O)(CR¹²R¹³)rR⁷, NR¹⁰C(O)(CR¹²R¹³)rOR⁷, NR¹⁰C(═NC)(CR¹²R¹³)rR⁷,NR¹⁰CO(CR¹²R¹³)rNR⁸R⁹, NR¹⁰(CR¹²R¹³)mOR⁷, NR¹⁰(CR¹²R¹³)rCO₂R₇,NR¹⁰(CR¹²R¹³)mNR⁸R⁹, NR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹⁵)qR⁷,CONR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴ R¹⁵)qR⁷, SO₂NR¹⁰(CR¹²R¹³)nCO(CR¹⁴R¹⁵)qR⁷, andSO₂NR¹⁰(CR¹²R¹³)mOR⁷.

[0450] The term “heterocycloalkyl” refers to substituted andunsubstituted saturated or partially saturated monocyclic rings of 3 to7 members and bicyclic rings of 7 to 11 members having one or two O or Satoms and/or one to four N atoms provided that the total number ofheteroatoms is four or less and that the heterocycloalkyl ring containsat least one carbon atom. The nitrogen and sulfur atoms may optionallybe oxidized, and the nitrogen atoms may optionally be quaternized. Thebicyclic heterocycloalkyl ring may also contain a two or three carbonbridge between available carbon or nitrogen atoms. The bicyclicheterocycloalkyl rings may also have a cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl ringfused to the monocyclic ring provided that the point of attachment isthrough an available carbon or nitrogen atom of the heterocycloalkylring. Also included are spiroheterocycloalkyl rings wherein a carbonatom of the heterocycloalkyl ring is in common with a secondheterocycloalkyl ring, a cycloalkyl ring, or a substituted cycloalkylring again provided that the point of attachment is through an availablecarbon or nitrogen atom of the heterocycloalkyl ring. Theheterocycloalkyl ring can have one, two or three substituents onavailable carbon or nitrogen atoms selected from the group consisting ofhalogen, nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl,heteroaryl, oxo, OR⁷, CO₂R⁷, C(O)NR⁸R⁹, OC(O)R⁷, OC(O)OR⁷, OC(O)NR⁸R⁹,OCH₂CO₂R⁷, C(O)R⁷, NR⁸R⁹, NR¹⁰C(O)R⁷, NR¹⁰C(O)OR⁷, NR¹⁰C(O)C(O)OR⁷,NR¹⁰C(O)C(O)NR⁸R⁹, NR¹⁰C(O)C(O)alkyl, NR¹⁰C(NCN)OR⁷, NR¹⁰C(O)NR⁸R⁹,NR¹⁰C(NCN)NR⁸R⁹, NR¹⁰C(NR¹¹)NR⁸R⁹, NR¹⁰SO₂NR⁸R⁹, NR¹⁰SO₂R⁷, SR⁷, S(O)R⁷,SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, NHOR⁷, NR¹⁰NR⁸R⁹, N(COR⁷)OR¹⁰, N(CO₂R⁷)OR¹⁰,C(O)NR¹⁰(CR¹²R¹³)_(r)R⁷, CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qCO₂R₇, CO(CR¹²R¹³)rOR⁷,CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qR⁷, CO(CR¹²R ¹³)rNR⁸R⁹, OC(O)O(CR¹²R¹³)mNR⁸R⁹,OC(O)N(CR¹²R¹³)rR⁷, O(CR¹²R¹³)mNR⁸R⁹, NR¹⁰C(O)(CR¹²R¹³)rR⁷,NR¹⁰C(O)(CR¹²R¹³)rOR⁷, NR¹⁰C(═NC)(CR¹²R¹³)rR⁷, NR¹⁰CO(CR¹²R¹³)rNR⁸R⁹,NR¹⁰(CR¹²R¹³mOR⁷, NR¹⁰(CR¹²R¹³)rCO₂R⁷, NR¹⁰(CR¹²R¹³)mNR⁸R⁹,NR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹⁵)qR⁷, CONR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹⁵)qR⁷,SO₂NR¹⁰(CR¹²R¹³)nCO(CR¹⁴R¹⁵)qR⁷, and SO₂NR¹⁰(CR¹²R¹³)mOR⁷.

[0451] Exemplary monocyclic heterocycloalkyl groups includepyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, oxetanyl,imidazolinyl, imidazolidinyl, oxazolidinyl, isothiazolidinyl,isoxazolinyl, thiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl,tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,tetrahydrothiopyranylsulfone, 1,3-dioxolanyl,tetrahydro-1,1-dioxothienyl, dioxanyl, thietanyl, thiiranyl,triazolinyl, triazolidinyl, etc.

[0452] Exemplary bicyclic heterocycloalkyl groups include indolinyl,quinuclidinyl, tetrahydroisoquinolinyl, benzimidazolinyl, chromanyl,dihydrobenzofuran, dihydrofuro[3,4-b] pyridinyl, dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),benzofurazanyl, benzotriazolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, dihydrobenzopyranyl, isoindolinyl, isochromanyl, benzodioxolyl,tetrahydroquinolinyl, etc.

[0453] Exemplary spirocyclic heterocycloalkyl groups include1-aza[4.5]spirodecane, 2-aza[4.5]spirodecane, 1-aza[5.5]spiroundecane,2-aza[5.5]spiroundecane, 3-aza[5.5]spiroundecane, etc.

[0454] The term “heteroaryl” refers to substituted and unsubstitutedaromatic 5 or 6 membered monocyclic groups and 9 or 10 membered bicyclicgroups which have at least one heteroatom (O, S or N) in at least one ofrings. Each ring of the heteroaryl groups containing a heteroatom cancontain one or two O and S atoms and/or from one to four N atomsprovided that the total number of heteroatoms in each ring is four orless. The bicyclic heteroaryl rings are formed by fusing a cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, orheteroaryl group to the monocyclic heteroaryl ring as defined above. Theheteroaryl group is attached via an available carbon or nitrogen in thearomatic heteroaryl ring. The nitrogen and sulfur atoms may optionallybe oxidized and the nitrogen atoms may optionally be quaternized. Theheteroaryl ring system may be substituted at an available carbon ornitrogen by one, two, or three substituents selected from the groupconsisting of halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl, heteroaryl, OR⁷, CO₂R⁷, C(O)NR⁸R⁹, OC(O)R⁷, OC(O)OR⁷,OC(O)NR⁸R⁹, OCH₂CO₂R C(O)R⁷, NR⁸R⁹, NR¹⁰C(O)R⁷, NR¹⁰C(O)OR⁷,NR¹⁰C(O)C(O)OR⁷, NR¹⁰C(O)C(O)NR⁸R⁹, NR¹⁰C(O)C(O)alkyl, NR¹⁰C(NCN)OR⁷,NR¹⁰C(O)NR⁸R⁹, NR¹⁰C(NCN)NR⁸R⁹, NR¹⁰C(NR¹¹)NR⁸R⁹, NR¹⁰SO₂NR⁸R⁹,NR¹⁰SO₂R⁷, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, NHOR⁷, NR¹⁰ NR⁸R⁹,N(COR⁷)OR¹⁰, N(CO₂R⁷)OR¹⁰, C(O)NR¹⁰(CR¹²R¹³)_(r)R⁷,CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qCO₂R₇, CO(CR¹²R¹³)rOR⁷,CO(CR¹²R¹³)pO(CR¹⁴R¹⁵)qR⁷, CO(CR¹²R¹³)rNR⁸R⁹, OC(O)O(CR¹²R¹³)mNR⁸R⁹,OC(O)N(CR¹²R¹³)rR⁷, O(CR¹²R¹³)mNR⁸R⁹, NR¹⁰C(O)(CR¹²R¹³)rR⁷,NR¹⁰C(O)(CR¹²R¹³)rOR⁷, NR¹⁰C(═NC)(CR¹²R¹³)rR⁷, NR¹⁰CO(CR¹²R¹³)rNR⁸R⁹,NR¹⁰(CR¹² R¹³)mOR⁷, NR¹⁰(CR¹²R¹³)rCO₂R₇, NR¹⁰ (CR¹²R¹³)mNR⁸R⁹,NR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹⁵)qR⁷, CONR¹⁰(CR¹²R¹³)nSO₂(CR¹⁴R¹⁵)qR⁷,SO₂NR¹⁰(CR¹²R¹³)nCO(CR¹⁴R¹⁵)qR⁷, and SO₂NR¹⁰(CR¹²R¹³)mOR⁷.

[0455] Exemplary monocyclic heteroaryl groups include pyrrolyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, furyl, thienyl, oxadiazolyl, 2-oxazepinyl,azepinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl,etc.

[0456] Exemplary bicyclic heteroaryl groups include benzothiazolyl,benzoxazolyl, benzothienyl, benzofuryl, quinolinyl, quinolinyl-N-oxide,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl or furo[2,3-b]pyridinyl),benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzothiopyranyl,benzotriazolyl, benzpyrazolyl, naphthyridinyl, phthalazinyl, purinyl,pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl,etc.

[0457] R¹² and R¹⁴ are independently selected from hydrogen and alkyl of1 to 4 carbons.

[0458] R¹³ and R¹⁵ are independently selected from hydrogen, alkyl of 1to 4 carbons, and substituted alkyl of 1 to 4 carbons.

[0459] n is zero or an integer from 1 to 4.

[0460] m is an integer from 2 to 6.

[0461] p is an integer from 1 to 3.

[0462] q is zero or an integer from 1 to 3.

[0463] r is zero or an integer from 1 to 6.

[0464] “IMPDH-associated disorders” refers to any disorder or diseasestate in which inhibition of the enzyme IMPDH (inosine monophosphatedehydrogenase, EC1.1.1.205, of which there are presently two knownisozymes referred to as IMPDH type 1 and IMPDH type 2) would modulatethe activity of cells (such as lymphocytes or other cells) and therebyameliorate or reduce the symptoms or modify the underlying cause(s) ofthat disorder or disease. There may or may not be present in thedisorder or disease an abnormality associated directly with the IMPDHenzyme. Examples of IMPDH-associated disorders include transplantrejection and autoimmune disorders, such as rheumatoid arthritis,multiple sclerosis, juvenile diabetes, asthma, and inflammatory boweldisease, as well as inflammatory disorders, cancer and tumor disorders,T-cell mediated hypersensitivity diseases, ischemic or reperfusioninjury, viral replication diseases, proliferative disorders and vasculardiseases.

[0465] As used herein the term “treating” includes prophylactic andtherapeutic uses, and refers to the alleviation of symptoms of aparticular disorder in a patient, the improvement of an ascertainablemeasurement associated with a particular disorder, or the prevention ofa particular immune response (such as transplant rejection). The term“patient” refers to a mammal, preferably a human.

[0466] The compounds of this invention may contain one or moreasymmetric carbon atoms and thus may occur as racemates and racemicmixtures, single enantiomers, diastereomeric mixtures and individualdiastereomers. All such isomers of the compounds disclosed herein areexpressly included within the scope of the present invention. Eachstereogenic carbon may be of the R or S configuration.

[0467] Combinations of substituents and variables thereof that result instable compounds are also contemplated within the present invention. Theterm “stable” as used herein refers to compounds which possess stabilitysufficient to allow manufacture and which maintain their integrity for asufficient period of time to be useful as a therapeutic or diagnosticagent.

[0468] As used herein, the compounds of this invention are defined toinclude pharmaceutically acceptable derivatives and prodrugs thereof. A“pharmaceutically acceptable derivative or prodrug” includes anypharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound of the present invention which, uponadministration to a subject, is capable of providing (directly orindirectly) a compound of the invention. Particularly favoredderivatives and prodrugs are those that increase the bioavailability ofthe compounds of the present invention when such compound isadministered to a subject (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species. Preferredprodrugs include derivatives where a group that enhances aqueoussolubility or active transport through the gut membrane is appended to acompound of the present invention.

[0469] Pharmaceutically acceptable salts of the compounds disclosedherein include those derived from pharmaceutically acceptable inorganicand organic acids and bases known to those skilled in the art. Examplesof suitable acid salts include, but are not limited to, the following:acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, trifluoroacetic, tosylate and undecanoate. Other acids, forexample oxalic, while not in themselves pharmaceutically acceptable, maybe employed in the preparation of salts useful as intermediates inobtaining the compounds of the present invention and theirpharmaceutically acceptable acid additional salts.

[0470] Salts derived from appropriate bases include, but are not limitedto, the following: alkali metal (e.g., sodium), alkaline earth metal(e.g., magnesium), ammonium and N-(C₁₋₄ alkyl)₄ ⁺ salts. The presentinvention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water- oroil-soluble or dispersible products may be obtained by suchquaternization.

Methods of Preparation

[0471] The compounds of the present invention may be synthesized usingconventional techniques known in the art. Advantageously, thesecompounds are conveniently synthesized from readily available startingmaterials. Following are general synthetic schemes for manufacturingcompounds of the present invention. These schemes are illustrative andare not meant to limit the possible techniques one skilled in the artmay use to manufacture compounds disclosed herein. Different methodswill be evident to those skilled in the art. Additionally, the varioussteps in the synthesis may be performed in an alternate sequence ororder to give the desired compound(s). All documents cited herein areincorporated herein by reference in their entirety.

[0472] Compounds of the present invention can be made by many methods,which will be known to one skilled in the art of organic chemistry. Ingeneral, the time taken to complete a reaction procedure will be judgedby the person performing the procedure, preferably with the aid ofinformation obtained by monitoring the reaction by methods such as HPLCor TLC. A reaction does not have to go to completion to be useful tothis invention. The preparation of heterocycles useful to this inventionare described in the series of books: “Comprehensive HeterocyclicChemistry, The Structure, Reactions, Synthesis and Uses, of HeterocyclicCompounds” Katritzky, A. R., Rees, C. W. Eds Pergamon Press New York,First edition 1984, and “Comprehensive Heterocyclic Chemistry II, AReview of the Literature 1982-1995. The Structure, Reactions, Synthesisand Uses, of Heterocyclic Compounds” Katritzky, A. R., Rees, C. W. andScriven, E., F. Eds Pergamon Press New York, 1996.

[0473] Amines such as anilines or heterocyclic amines, useful for thepreparation of compounds useful to this invention may be commerciallyavailable or readily prepared by many methods known to one skilled inthe art of organic chemistry, and are described in “ComprehensiveOrganic Transformations A Guide to Functional Group Preparation” pp385-439. Richard C. Larock 1989 VCH Publishers, Inc. Examples includebut are not limited to reduction of a nitro group, and reduction of anazide. Methods for the production of amines useful to this invention areoutlined in Schemes 1a-1f.

[0474] A general method for the synthesis of the anilines such as (1a.4)useful in this invention can be perfomed by metal catalyzed crosscoupling methods known in the literature. The simplest case is a Suzukitype cross coupling (Miyaura, N., Yanagi, T. Suzuki, A., Synth. Comm.11(7):513-519 (1981); A. Suzuki et. al., J. Am. Chem. Soc. 111:513(1989); and V. N. Kalinin, Russ. Chem. Rev. 60:173 (1991)) of an arylboronic acid or ester (1a.1) (as shown below) with an appropriatebromoheterocycle in the presence of a suitable catalyst such as tetrakis(triphenylphosphine) palladium. After the cross coupling has beenperformed the product may be deprotected. The choice of protecting groupand its method of removal will be readily apparent to one skilled in theart of organic chemistry. Such considerations and methods are, forexample, described by Greene, Theodora W. and Wuts, Peter G. M. in“Protective Groups in Organic Synthesis.” 2nd Ed., (1991) Publisher:(John Wiley and Sons, Inc., New York, N.Y. For example, if theprotecting group is acetyl the product may be deprotected by treatmentwith aqueous potassium hydroxide at a concentration of 0.5N to 5 N atroom temperature to 100° C. for a period between 0.5 h and 24 h.

[0475] For example aryl boronic acid (1a.5) may react with the known5-bromothiazole (1a.6) in the presence of tetrakis(triphenylphosphine)palladium (0), to provide (1a.7) which may be deprotected by anappropriate method.

[0476] Copper has been recently been shown to be an effective catalystfor cross coupling of aryl boronic acids to N-unsubstituted heterocyclesas described by Chan et al., Tetrahed. Lett. 39:2933-2936 (1998); andLam et al., Tetrahed. Lett. 39:2941-2944 (1998). This results incompounds in which the heterocycle is attached to the aryl ring throughnitrogen rather than carbon. For example aryl boronic acid (1a.5) mayreact with oxazolone (1a.8) in the presence of copper (II) acetate inthe presence of an amine base such as pyridine to provide intermediate(1a.9) which may be deprotected by an appropriate method

[0477] In general aryl boronic acids and esters, 1b.3, where X is not Bror I, may be prepared as shown in Scheme Ib, from the correspondingarylbromide (1b.1) by treatment with a palladium catalyst such as[1,1′-Bis(diphenylphosphino)-ferrocene] dichloropalladium (II) andbis(pinacolato)diboron, (1b.2), as reported by Ishayama et al., J. Org.Chem., (1995) 7508-7510. Aryl boronic esters may be converted to thecorresponding boronic acid by several methods including treatment withaqueous HCl. In a variation of the synthesis, the nitrogen may be maskedas a nitro group and later reduced by several means including metalreductions, such as by treatment with tin chloride in HCl or byrefluxing the nitro compound with zinc in the presence of CaCl₂ in asolvent such as ethanol, or in certain cases the nitro group may bereduced by catalytic hydrogenation in the presence of catalysts such aspalladium on carbon. The conditions for the reduction of nitro groupsare detailed in several references including Hudlicky, M., “Reductionsin Organic Chemistry”, 2nd Ed., ACS Monograph 188, 1996, pp 91-101,American Chemical Society, Washington, D.C. A second variation of thesynthesis allows the aryl bromide to remain through the entire synthesisand elaborated to the boronic acid at the end. This may eliminate theneed for a protecting group.

[0478] In certain cases it may be more expedient to construct theheterocyclic ring by other methods. A general method for the synthesisof 5-membered heterocycles includes the 1,3-dipolar cycloadditionreaction, which is well known to one skilled in the art of organicchemistry and is described by Padwa, Albert, Editor in “1,3-DipolarCycloaddition Chemistry, Vol. 2” (1984) John Wiley and Sons, New York,N.Y.; and Padwa, Albert; Editor. in “1,3-Dipolar CycloadditionChemistry, Vol. 1” (1984) John Wiley and Sons, New York, N.Y. Forexample oxazoles may be prepared by 1,3 dipolar cycloaddtion of thecorresponding aldehyde (1c.1) and (p-tolylsulfonyl)methyl isocyanate(TOSMIC) (1c.2) as shown in scheme Ic. The aldehyde may be commerciallyavailable or prepared from the corresponding methyl group by oxidationwith reagents such as CrO₃, MnO₂, and ammonium cerium (IV) nitrate bymethods well known to one skilled in the art of organic chemistry and isdescribed in Hudlicky, M., “Oxidations in Organic Chemistry”, ACSMonograph 186 (1990), American Chemical Society, Washington, D.C. Thenitro group in intermediate (1c.3), is reduced to an amine (1c.4), asdiscussed above.

[0479] An alternative method of producing amines useful to thisinvention is by nucleophilic attack on an electron deficient ring systemas outlined in Scheme 1d. Halonitrobenzenes (1d.1), are eithercommercially available or readily prepared by methods known to oneskilled in the art of organic synthesis. Displacement with a variety ofnucleophiles produce compounds of structure (1d.2). In one exampleheating (1d.3) with a nucleophilic heterocycle such as triazole with orwithout the addition of a base provides the intermediate nitro compoundwhich may be reduced as previously described to provide amines (1d.4).Alternatively simple organic nucleophiles such as cyanide can be reactedwith halonitrobenzene (1d.5) to provide an intermediate nitrocompoundwhich can be reduced by many methods to an amine (1d.6).

[0480] In some cases it will be useful to have an ortho-bromo orortho-iodo aniline as an intermediate for the synthesis of heterocyclesuseful for this invention as described in scheme Ie. Bromination ofanilines may be accomplished in many cases by simply dissolving theaniline, such as (1a.4) and (1c.4), in a suitable solvent such asmethylene chloride, chloroform, acetic acid or hydrochloric acid, andtreating with one equivalent of bromine, at a temperature from −78 to40° C. to provide aniline (1e.1 and 1e.2). In some cases the aniline maybe protected with a group such as acetate. In this case the brominationcan often be accomplished by the addition of a Lewis acid catalyst suchas iron, or FeBr₃. Iodination can be effected in a manner analogous tothat described for bromine, but may also benefit from the addition ofsilver salts such as silver benzoate, silver triflate, silvertrifluoroacetate, or periodic acid, to provide aniline (1e.3) and(1e.4).

[0481] The synthesis of useful aniline intermediates which contain anortho keto group (1f.3) is depicted in Scheme 1f. They may be preparedfrom anilines (1e.1) and (1e.2, shown) by palladium mediated coupingwith an appropriate alkoxyvinyl stannane (1f.1) to produce theenol-ether (1f.2). Hydrolysis of the enol-ether with dilute acidprovides the ketone (1f.3)

[0482] In the case where the compounds useful; for this invention arequinolines they may be conveniently prepared from the correspondinganilines via several methods including those outlined in Scheme 2a,through 2c.

[0483] In scheme 2a, aniline (2a.1), (of which anilines (1a.4) and(1c.4) are examples) is heated in an inert solvent such as toluene,xylene, or diphenylether at a temperature up to the boiling point of thesolvent with a β-ketoester (2a.2) to provide quinolone (2a.3). Thismethod of quinolone synthesis has been described in the literature, forexample see Kuo et al. in J. Med. Chem 1993, 36, 1146-1156. In somecases this cyclization can be aided by the use of an acid such aspolyphosphoric acid or sulfuric acid to facilitate the intramolecularFriedel-Crafts acylation. In some cases isomereric cyclization productsmay be formed. In general these may be separated by flash columnchromatography or high performance liquid chromatography.

[0484] A modification of the above the synthesis has been reported byToda, J. et al. in Heterocycles 1994, 38, 2091-2097. In this method thebeta keto ester (2a.2) is converted to an enamine (2a.4) by refluxingwith an amine such as methylamine in an alcoholic solvent in thepresence of acetic acid. The enamine (2a.4) is then reacted with ananiline such as (2a.1) in an inert solvent such as benzene, methylenechloride, or carbon tetrachloride in the presence of an equivalent ofpyridinium p-toluenesulfonate (PPTS) to effect an N—N exchange reactionto produce enamine (2a.5). This can be cyclized to the quinolone byheating in an inert solvent such as xylene at a temperature between150-300° C. In some cases, as mentioned above, an acid catalyst may beadded to aid in the intramolecular Friedel-Crafts acylation.

[0485] β-ketoesters such as (IIa.2) useful for this invention are eithercommercially available or readily prepared from the correspondingcarboxylic acids or esters by several means including, that reported byClay, R. J., et al., in Synthesis, 1993, 290-292, and those outlined inchapter 2 of “Advanced Organic Chemistry” ₃rd edition (1990) by Carey,F. A., and Sundberg R. J., Plenum Press, New York, N.Y.

[0486] An alternative quinolone synthesis starting from aniline (1e.3)(of which aniline 1e.4 is an example) is depicted in Scheme 2b. Thismethod of quinolone synthesis has been described in the literature, forexample see Kalinin, V. N., et. al. Tetrahedron Lett. 1992, 33, 373-376,and Torii, S., et. al. in Tetrahedron 1993, 42, 6773-6784. The aniline(1e.3) is heated between 60-160° C. in the presence of an acetylene(2d.1) and 0.1-5 mol % of a palladium catalyst such astetrakistriphenylphosphine palladium (0), dichlorobis(triphenylphosphine)palladium (II), ordichloro[1,1′-bis(diphenylphosphino)ferrocene palladium (II), in anatmosphere of carbon monoxide (3-40 atmospheres) in a steel autoclave.

[0487] Acetylenes 2d.1 are either commercially available or may beprepared by several methods including, palladium catalyzed coupling withan aryl or vinyl bromide or iodide with trimethylsilylacetylene asinitially described by Takahashi, S. et. al. in Synthesis 1980, 627. Thetrimethylsilyl protecting group may be removed by treatment with aqueousbase or with a fluoride source such as tetrabutylammonium fluoride. Analternative sythesis of terminal acetylenes is commonly known as theCorey-Fuchs sythesis, for examples see Wang, Z. et al. J.Org. Chem.2000,65, 1889-91, and references contained therein. The Corey-Fuchs synthesesand its modifications start with an appropriately substituted aldehyde.The aldehydes useful for this invention are either commerciallyavailable or readily prepared by oxidation of an alcohol by many methodsas described by Hudlicky, M. “Oxidations in Organic Chemistry”, ACSMonograph 186, 1990, American Chemical Society, Washington, D.C.

[0488] Another alternative synthesis of quinolones has been reported inthe literature for example see, Li, L., et al. in J. Med. Chem. 1994,37, 3400-3407, and is depicted in Scheme 2c. Aniline (1f.3) is coupledwith an carboxylic acid (2c.1) to form an amide (2c.2). The coupling iscarried out using any of the many methods for the formation of amidebonds known to one skilled in the art of organic synthesis. Thesemethods include but are not limited to conversion of the acid to thecorresponding acid chloride, or use of standard coupling procedures suchas the azide method, mixed carbonic acid anhydride (isobutylchloroformate) method, carbodiimide (dicyclohexylcarbodiimide,diisopropylcarbodiimide, or water-soluble carbodiimides) method, activeester (p-nitrophenyl ester, N-hydroxysuccinic imido ester) method,carbonyldiimidazole method, phosphorus reagents such as BOP-Cl. Some ofthese methods (especially the carbodiimide) can be enhanced by theaddition of 1-hydroxybenzotriazole. The amide (2c.2) is then treatedwith a base such as potassium tert-butoxide to effect cyclization to thequinolone (2c.3).

[0489] The the synthesis of dioxides of benzothiazines (3a.2) has beenreported in the literature, for example see, Florio at al. in J. Chem.Soc. Perkin Trans. I. 1984, 1899-1903. This chemistry is depicted inscheme 3a.

[0490] An alternative synthesis of benzothiazines (3b.3) andbenzothiadiazines (3b.5) has been reported in the literature, forexample, Vysokov et al. in Russian J. of Org. Chem. 1998, 34, 428-433.This chemistry is depicted in scheme 3b.

[0491] The synthesis of substituted-3-hydroxy quinolinones (4a.3) hasbeen reported in the literature, for example, Hradil et al. J.Heterocyclic Chem. 1999, 36, 141-144. This chemistry is depicted inscheme 4a.

[0492] An alternative synthesis of substituted-3-hydroxy quinolinones(4b.4) has been reported in the literature, for example, Sui et al. Eur.J. Chem. 1999, 34, 381-387. This chemistry is depicted in scheme 4b. Adirect conversion of 4-quinolones into 3-hydroxy-4-quinolones has beenreported in the liturature, for example, Behrman et al, J. Chem Research1995, 164-165.

[0493] A versatile synthesis of quinolones was reported in theliterature, by Chen et al, Synthesis, 1987, 482-483. The chemistry isshown in scheme 5a. Examples described herein such as Example 160 wereprepared by a similar route.

[0494] Acids (2c.1) useful for this invention in their own right or forthe preparation of beta ketoesters such as (2a.2) are eithercommercially available or readily prepared by a number of methods knownto one skilled in the art of orgainic chemistry including, oxidation ofan alcohol or hydrolysis of an ester. Transformations that produce acidsfrom commercially available reagents are described by Larock, R. C. in“Comprehensive Organic Transformations: a Guide to Functional GroupPreparations.” 1989, VCH Publishers, N.Y., N.Y.

[0495] The compounds of the present invention may be modified byappending appropriate functionalities to enhance selective biologicalproperties. Such modifications are known in the art and include thosewhich increase biological penetration into a given biologicalcompartment (e.g., blood, lymphatic system, central nervous system),increase oral availability, increase solubility to allow administrationby injection, alter metabolism and alter rate of excretion.

Utility

[0496] The compounds of the present invention inhibit IMPDH enzyme, andare thus useful in the treatment, including prevention and therapy ofdisorders which are mediated or effected by cells which are sensitive toIMPDH inhibition, as described previously. The present invention thusprovides methods for the treatment of IMPDH-associated disorders,comprising the step of administering to a subject in need thereof atleast one compound of the formula I, preferably at least one compoundrepresented by formulas II and/or III, in an amount effective therefor.Other therapeutic agents, such as those described below, may be employedwith the inventive compounds in the present methods. In the methods ofthe present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with or following theadministration of the compound(s) of the present invention.

[0497] The compounds of the present invention can be used in treating arange of disorders exemplified by, but not limited to, disorders suchas: the treatment of transplant rejection (e.g., kidney, liver, heart,lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel,skin allografts, skin homografts (such as employed in burn treatment),heart valve xenografts, serum sickness, and graft vs. host disease, inthe treatment of autoimmune diseases, such as rheumatoid arthritis,psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma,inflammatory bowel disease (such as Crohn's disease and ulcerativecolitus), pyoderma gangrenum, lupus (systemic lupus erythematosis),myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema,seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave'sdisease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's orSjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolyticanaemia, Addison's disease (autoimmune disease of the adrenal glands),idiopathic adrenal insufficiency, autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome), glomerulonephritis,scleroderma, morphea, lichen planus, viteligo (depigmentation of theskin), alopecia areata, autoimmune alopecia, autoimmune hypopituatarism,Guillain-Barre syndrome, and alveolitis; in the treatment of T-cellmediated hypersensitivity diseases, including contact hypersensitivity,delayed-type hypersensitivity, contact dermatitis (including that due topoison ivy), uticaria, skin allergies, respiratory allergies (hayfever,allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease); inthe treatment of inflammatory diseases such as osteoarthritis, acutepancreatitis, chronic pancreatitis, asthma, acute respiratory distresssyndrome, Sezary's syndrome and vascular diseases which have aninflammatory and or a proliferatory component such as restenosis,stenosis and artherosclerosis; in the treatment of cancer and tumordisorders, such as solid tumors, lymphomas and leukemia; in thetreatment of fungal infections such as mycosis fungoides; in protectionfrom ischemic or reperfusion injury such as ischemic or reperfusioninjury that may have been incurred during organ transplantation,myocardial infarction, stroke or other causes; and in the treatment ofDNA and RNA viral replication diseases, such herpes simplex type 1(HSV-1), herpes simplex type 2 (HSV-2), hepatitis (including hepatitis Band hepatitis C), cytomegalovirus, Epstein-Barr, and humanimmunodeficiency virus (HIV).

[0498] Additionally, IMPDH is also known to be present in bacteria andthus may regulate bacterial growth. As such, the IMPDH-inhibitorcompounds of the present invention may be useful in treatment orprevention of bacterial infection, alone or in combination with otherantibiotic agents.

[0499] In a particular embodiment, the compounds of the presentinvention are useful for the treatment of the aforementioned exemplarydisorders irrespective of their etiology, for example, for the treatmentof transplant rejection, rheumatoid arthritis, inflammatory boweldisease, and viral infections.

[0500] The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of formula I, preferably atleast one of the compounds of formulas II and/or III, or a salt thereof,capable of treating an IMPDH-associated disorder in an amount effectivetherefor, alone or in combination with at least one additionaltherapeutic agent, and any pharmaceutically acceptable carrier, adjuvantor vehicle. “Additional therapeutic agents” encompasses, but is notlimited to, an agent or agents selected from the group consisting of animmunosuppressant, an anti-cancer agent, an anti-viral agent, ananti-inflammatory agent, an anti-fungal agent, an antibiotic, or ananti-vascular hyperproliferation compound.

[0501] The term “pharmaceutically acceptable carrier, adjuvant orvehicle” refers to a carrier, adjuvant or vehicle that may beadministered to a subject, together with a compound of the presentinvention, and which does not destroy the pharmacological activitythereof. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of the presentinvention include, but are not limited to, the following: ionexchangers, alumina, aluminum stearate, lecithin, self-emulsifying drugdelivery systems (“SEDDS”) such as d(-tocopherol polyethyleneglycol 1000succinate), surfactants used in pharmaceutical dosage forms such asTweens or other similar polymeric delivery matrices, serum proteins suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β- and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be used to enhance delivery of the compounds of the presentinvention.

[0502] The compositions of the present invention may contain othertherapeutic agents as described below, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

[0503] The compounds of the formula I may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; buccally; parenterally,such as by subcutaneous, intravenous, intramuscular, or intrasternalinjection or infusion techniques (e.g., as sterile injectable aqueous ornon-aqueous solutions or suspensions); nasally such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds may, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release may be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds mayalso be administered liposomally.

[0504] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The present compounds mayalso be delivered through the oral cavity by sublingual and/or buccaladministration. Molded tablets, compressed tablets or freeze-driedtablets are exemplary forms which may be used. Exemplary compositionsinclude those formulating the present compound(s) with fast dissolvingdiluents such as mannitol, lactose, sucrose and/or cyclodextrins. Alsoincluded in such formulations may be high molecular weight excipientssuch as celluloses (avicel) or polyethylene glycols (PEG). Suchformulations may also include an excipient to aid mucosal adhesion suchas hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose(HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydridecopolymer (e.g., Gantrez), and agents to control release such aspolyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use.

[0505] Exemplary compositions for nasal aerosol or inhalationadministration include solutions in saline which may contain, forexample, benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

[0506] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

[0507] Exemplary compositions for rectal administration includesuppositories which may contain, for example, a suitable non-irritatingexcipient, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures, butliquify and/or dissolve in the rectal cavity to release the drug.

[0508] Exemplary compositions for topical administration include atopical carrier such as Plastibase (mineral oil gelled withpolyethylene).

[0509] The effective amount of a compound of the present invention maybe determined by one of ordinary skill in the art, and includesexemplary dosage amounts for an adult human of from about 0.1 to 500mg/kg of body weight of active compound per day, which may beadministered in a single dose or in the form of individual divideddoses, such as from 1 to 5 times per day. It will be understood that thespecific dose level and frequency of dosage for any particular subjectmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the species, age, body weight,general health, sex and diet of the subject, the mode and time ofadministration, rate of excretion, drug combination, and severity of theparticular condition. Preferred subjects for treatment include animals,most preferably mammalian species such as humans, and domestic animalssuch as dogs, cats and the like, subject to IMPDH-associated disorders.

[0510] The compounds of the present invention may be employed alone orin combination with each other and/or other suitable therapeutic agentsuseful in the treatment of IMPDH-associated disorders, such as IMPDHinhibitors other than those of the present invention,immunosuppressants, anti-cancer agents, anti-viral agents,anti-inflammatory agents, anti-fungal agents, antibiotics, oranti-vascular hyperproliferation agents.

[0511] Exemplary such other therapeutic agents include the following:cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such asanti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2,anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibodyOKT3, agents blocking the interaction between CD40 and CD154 (a.k.a.“gp39”), such as antibodies specific for CD40 and/or CD154, fusionproteins constructed from CD40 and/or CD154/gp39 (e.g., CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappaB function, such as deoxyspergualin (DSG), non-steroidalantiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib androfecoxib, steroids such as prednisone or dexamethasone, gold compounds,antiviral agents such as abacavir, antiproliferative agents such asmethotrexate, leflunomide, FK506 (tacrolimus, Prograf), cytotoxic drugssuch as azathiprine and cyclophosphamide, TNF-α inhibitors such astenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin(sirolimus or Rapamune) or derivatives thereof.

[0512] The above other therapeutic agents, when employed in combinationwith the compounds of the present invention, may be used, for example,in those amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

[0513] The compounds disclosed herein are capable of targeting andinhibiting IMPDH enzyme. Inhibition can be measured by various methods,including, for example, IMP dehydrogenase HPLC assays (measuringenzymatic production of XMP and NADH from IMP and NAD) and IMPdehydrogenase spectrophotometric assays (measuring enzymatic productionof NADH from NAD). See, e.g., Montero et al., Clinica Chimica Acta238:169-178 (1995). Additional assays known in the art can be used inascertaining the degree of activity of a compound (“test compound”) asan IMPDH inhibitor. The inventors used the following assay to determinethe degree of activity of the compounds disclosed herein as IMPDHinhibitors:

[0514] Activity of IMPDH I and IMPDH II was measured following anadaptation of the method described in WO 97/40028. The reaction mixturewas prepared containing 0.1M Tris pH 8.0, 0.1 M KC1, 3 mM EDTA, 2 mMDTT, 0.4 mM IMP and 40 nM enzyme (IMPDH I or IMPDH II). The reaction wasstarted by the addition of NAD to a final concentration of 0.4 mM. Theenzymatic reaction was followed by measuring the increase in absorbanceat 340 nM that results from the formation of NADH. For the analysis ofpotential inhibitors of the enzyme, compounds were dissolved in DMSO toa final concentration of 10 mM and added to the assay mixture such thatthe final concentration of DMSO was 2.5%. The assay was carried out in a96-well plate format, with a final reaction volume of 200 □l.

[0515] The compounds disclosed herein are capable of inhibiting theenzyme IMPDH at a measurable level, under the above-described assay oran assay which can determine an effect of inhibition of the enzymeIMPDH.

[0516] The following examples illustrate preferred embodiments of thepresent invention and do not limit the scope of the present inventionwhich is defined in the claims. Abbreviations employed in the Examplesare defined below. Compounds of the Examples are identified by theexample and step in which they are prepared (e.g., “1A” denotes thetitle compound of step A of Example 1), or by the example only where thecompound is the title compound of the example (for example, “2” denotesthe title compound of Example 2). Abbreviations Ac Acetyl AcOH Aceticacid aq. Aqueous CDI Carbonyldiimidazole Bn Benzyl Boctert-butoxycarbonyl DMAP Dimethylaminopyridine DMF dimethylformamideDMSO Dimethylsulfoxide EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc Ethyl acetate Et Ethyl EtOHEthanol h Hours i iso HPLC High pressure liquid chromatography HOAcAcetic acid THF Tetrahydrofuran Lawesson's Reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia- 2,4-diphosphetane-2-4-disufide LCliquid chromatography Me Methyl MeOH Methanol min. Minutes M⁺ (M + H)⁺M⁺¹ (M + H)⁺ MS Mass spectrometry n normal Pd/C Palladium on carbon PhPhenyl PPTS Pyridinium p-toluenesulfonate Pr Propyl p-TsOHpara-Toluenesulonic acid Ret Time Retention time rt or RT Roomtemperature sat. Saturated TFA Trifluoroacetic acid THF Tetrahydro furanTOSMIC Tosylmethyl isocyanide YMC YMC Inc, Wilmington, NC 28403

EXAMPLE 1 7-Methoxy-6-(5-oxazolyl)-2-phenyl-4(1H)-quinolinone

[0517]

Example 1 Part A 4-Nitro-2-methoxy-(α,α bisacetoxy)toluene

[0518]

[0519] 1A

[0520] To a 5 L three necked round bottom flask equipped with amechanical stirrer was added 4-nitro-2-methoxytoluene (150.0 g, 0.8973mol), HOAc (900 mL) and Ac₂O (900 mL) The mixture was stirred and cooledto 8° C. with an acetone/ice bath. Concentrated H₂SO₄ (136 mL) wascarefully added while keeping the reaction temperature below 19° C.After cooling to 0° C., CrO₃ (252.6 g, 2.526 mol, 2.815 equiv.) wasadded portion-wise over 1 hour while maintaining the reactiontemperature between 0-10° C. After the addition, the mixture was stirredat 0° C. for 30 minutes at which time the reaction was complete. Thereaction mixture was then carefully poured into ice (1.5 kg) withstirring to give a slurry. The remaining black gummy residue was rinsedwith HOAc (3×100 mL), and the washes were added to the slurry. Afterstirring for 10 minutes, the slurry was filtered. The cake was washedwith water (3×400 mL) and suction dried for 17 hours to 1A (129.0 g,51%). ¹H NMR (CDCl₃) □ 8.02 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.77 (s,1H), (d, 8.4 Hz, 1H), 3.98 (s, 3H), 2.16 (s, 6H).

Example 1, Part B 4-Nitro-2-methoxybenzaldehyde

[0521]

[0522] To a 2 L rounded bottom flask equipped with a condenser and amechanical stirrer was placed 1A (250.7 g, 0.8851 mol), dioxane (300 mL)and concentrated HCl (60 mL). The reaction mixture was heated to refluxand stirred under N₂ for 20 hours. Water (250 mL) was added dropwisewhile maintaining the reaction mixture at reflux. After cooling to 0° C.with an ice/water bath, the resulting slurry was stirred for 30 minutesand then filtered. The cake was washed with water (4×200 mL) and suctiondried for 17 hours to give 1B (146.3 g, 91%) as a yellow solid. ¹H NMR(CDCl₃) □ 10.54 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.89 (d,J=8.3 Hz, 1H), 4.08 (s, 3H)

Example 1 Part C 5-(4-Nitro-2-methoxyphenyl)oxazole

[0523]

[0524] To a 5 L three necked round bottom flask equipped with acondenser and a mechanical stirrer was placed 1B (146.3 g, 0.8076 mol),TOSMIC (157.7 g, 0.8077 mol), K₂CO₃ (116.6 g, 0.8075 mol) and MeOH (2.5L). The mixture was heated to reflux under N₂ and stirred for 3 hours.Water (1.25 L) was added drop-wise while maintaining the pot temperaturebetween 59-69° C. The resulting slurry was cooled to room temperature,and then to 5° C. with an ice-water bath. After stirring for 30 minutesat 5° C., the slurry was filtered. The resulting cake was washed withwater (3×400 mL) and dried in a vacuum oven at 45° C. for 20 hours to 1C(148.5 g, 84%) as a yellow-reddish solid. ¹H NMR (CDCl₃) □ 8.02 (s, 1H),7.97 (d, J=2 Hz, 1H), 7.95 (d, J=2 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 1H),4.11 (s, 3H).

Example 1, Part D 5-(4-Amino-2-methoxyphenyl)oxazole

[0525]

[0526] In a 2 L hydrogenation flask was placed 1C (130.0 g, 0.6131mol),Pd/C (10%, 26.2 g) and absolute EtOH (1280 mL). The mixture washydrogenated at 35-45 psi H₂ until the reaction was complete. Themixture was filtered over a pad of celite (20 g) and the cake was washedwith EtOH (3×100 mL). The filtrate was concentrated to a volume of 350mL. Heptane (500 mL) was added to the resulting slurry. After stirringfor 2 hours at room temperature, the slurry was filtered. The cake waswashed with heptane (3×100 mL) and air-dried to give 1D (80.0 g). Asecond portion of product (30.2 g) was recovered from the mother liquoraffording a total yield of 95%. ¹H NMR (CDCl₃) □ 7.88 (s, 1H), 7.60 (d,J=8.4 Hz, 1H), 7.41 (s, 1H), 6.41 (dd, J=8.4, 2.1 Hz, 1H), 3.34 (d,J=2.1 Hz, 1H), 3.98 (bs, 2H), 3.94 (s, 3H).

Example 1, Part E3-[3-methoxy-4-(5-oxazolyl)phenyl]amino]-3-phenyl-2-propenoic acid Ethylester

[0527]

[0528] A mixture of 3-methoxy-4-(5-oxazolyl)aniline, 1D, (1.00 g; 5.26mmol), ethyl benzoylacetate (0.91 mL; 5.26 mmol), and p-toluenesulfonicacid (0.10 g; 0.526 mmol) in 55 mL of dry toluene was heated at refluxin a Dean-Stark apparatus overnight. During this time a precipitateformed. The reaction mixture was cooled to room temperature and filteredto give 1F and small amount of p-toluenesulfonic acid. The filtrate wasconcentrated under reduced pressure, diluted with dichloromethane, andwashed with water. The organic layer was collected and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica chromatography toprovide 0.487 g of 1E as a pale yellow semi-solid. Analytical HPLCretention time=4.08 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic;Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O,0.2% H₃PO₄) with a LC/MS M⁺¹=365.23.

Example 1, Part F 7-Methoxy-6-(5-oxazolyl)-2-phenyl-4(1H)-quinolinone

[0529] 1E was heated in 4 mL of xylene in a sealed tube at 250° C.overnight. During this time, a precipitate was formed. The reactionmixture was cooled to room temperature, and the precipitate wascollected by vacuum filtration, washed with dichloromethane, and driedthoroughly to give 281 mg of 1F as a white solid. The filtrate containedadditional amounts of the product and starting material 1E. The productwas 99% pure by analytical HPLC with a retention time 2.71 min. (Column:YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄;Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS M⁺¹=319.14. 1H-NMR(400 mHz, DMSO) □ 4.05 (s, 3H), 6.34 (s, 1H), 7.38 (s, 1H), 7.59-7.61(m, 4H), 7.84-7.85 (m, 2H), 8.40 (s, 1H), 8.50 (s, 1H), and 11.72 (s,1H).

EXAMPLE 2 2-(3-Bromophenyl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0530]

Example 2 Part A 3-(3-Bromophenyl)-3-oxopropanoic Acid Ethyl Ester

[0531]

[0532] To potassium ethyl malonate (3.25 g, 19.13 mmol) in acetonitrile(50 mL) was sequentially added triethyl amine (4.1 mL, 29.16 mmol) andmagnesium chloride (2.16 g, 22.78 mmol) at room temperature. Afterstirring the reaction mixture at room temperature for 2 hours,3-bromobenzoyl chloride (2.0 g, 9.11 mmol) was added and the mixture washeated at 60° C. for 18 hours, concentrated under reduced pressure andpartitioned between ethyl acetate (100 mL) and 1N HCl (25 mL). The ethylacetate layer was dried over sodium sulfate and concentrated underreduced pressure to yield the title compound (2.45 g, 99%). ¹H NMR(CDCl₃): δ 8.1 (s, 1H), 7.85 (d, 1H), 7.7 (d, 1H), 7.35 (t, 1H), 4.3 (m,2H), 3.4 (s, 1H), 1.3 (m, 3H).

Example 2 Part B 3-(3-Bromophenyl)-3-(methylamino)-2-propenoic AcidEthyl Ester

[0533]

[0534] To a solution of 2A (2.5 g, 9.22 mmol) in ethyl alcohol (15 mL)was added methyl amine (2.0M in methyl alcohol, 23 mL, 46.12 mmol) andacetic acid (2.63 mL, 46.12 mmol). The reaction mixture was heated underreflux for three hours, cooled to room temperature and partitionedbetween ethyl acetate (50 mL) and water (100 mL). The ethyl acetatelayer was dried over sodium sulfate and concentrated under reducedpressure to yield the title compound (2.45 g, 93%) as an oil. ¹H NMR(CDCl₃): δ 8.4 (brs, 1H), 7.4 (m, 2H), 7.2 (m, 2H), 4.6 (s, 1H), 4.2 (q,2H), 2.8 (d, 3H), 1.2 (t, 3H).

Example 2, Part C3-[3-methoxy-4-(5-oxazolyl)phenyl]amino]-3-phenyl-2-propenoic Acid EthylEster

[0535]

[0536] To a solution of 2B (2.45 g, 8.68 mmol) in dichloromethane (50mL) was added aniline 1D (1.5 g, 7.89 mmol) and pyridiniumpara-toluenesulfonate (2.2 g, 8.68 mmol). The reaction mixture washeated under reflux for 24 hours and stirred at room temperature for 40hours. The solid that separates out was filtered and washed withdichloromethane (20 mL). The filtrate was concentrated under reducedpressure and purified by flash column chromatography employinghexane-ethyl acetate (6:4) as the eluent, to yield the title compound asa syrup (3.0 g, 85.7%). ¹H NMR (CDCl₃): δ 10.3 (s, 1H), 7.8 (s, 1H), 7.6(s, 1H), 7.5 (m, 2H), 7.4 (s, 1H), 7.25 (1H), 7.2 (m, 1H), 6.3 (d, 1H),6.2 (s, 1H), 5.1 (s, 1H), 4.3 (q, 2H), 3.65 (s, 3H), 1.2 (t, 3H).

Example 2, Part D2-(3-Bromophenyl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0537] A solution of 2C (3.0 g, 6.77 mmol) in ortho-xylene (25 mL) washeated to 240° C. in a sealed tube for three hours. The reaction mixturewas cooled to room temperature and the solid that separates out wasfiltered, washed with ethyl acetate (60 mL) and dried to yield the titlecompound as a solid (2.1 g, 78.1%). ¹H NMR (DMSO): δ 8.6 (s, 1H)<8.5 (s,1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.5 (t, 1H),7.4 (m,1H), 6.6 (s, 1H) 4.1 (s, 3H). LC/MS (retention time=3.11 min.; M⁺398. Column: YMC ODSA S5 C18 4.6×50 mm (4 min. gradient. Solvent A=10%MeOH, 90% H₂O, 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, 0.1% TFA).

EXAMPLE 37-Methoxy-2-[3-(1-pyrrolidinyl)phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0538]

Example 3 Part A2-(3-Bromophenyl)-7-methoxy-4-methoxymethoxy-6-(5-oxazolyl)quinoline

[0539]

[0540] Quinolone 2 (0.3 g, 0.75 mmol) in dimethylformamide (10 mL) wascooled to 0° C. and sodium hydride (0.023 g, 0.90 mmol) was added over athree minute period. The reaction mixture was stirred at 0° C. fortwenty minutes and heated at 80° C. for twenty minutes. The mixture wasbought to room temperature and chloromethyl methyl ether (68 μL, 0.90mmol) was added over three minutes. The reaction mixture was heated at80° C. for ten minutes and concentrated under reduced pressure. To theresidue that was obtained, water (20 mL) was cautiously added and thesolid that separates out was filtered and dried (0.33 g, 100%). LC/MS(retention time=3.03 min.; M⁺ 441.21. Column: YMC ODSA S5 C18 4.6×50 mm(4 min. gradient. Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; Solvent B=90%MeOH, 10% H₂O, 0.1% TFA).

Example 3 Part B2-[3-(1-pyrrolidinyl)phenyl]-7-methoxy-4-methoxymethoxy-6-(5-oxazolyl)quinoline

[0541]

[0542] To a solution of 3A (0.125 g, 0.28 mmol) in toluene (2 mL) wassequentially added tris(dibenzylideneacetone)dipalladium (0) (1 mg),S(−)BINAP (2 mg), cesium carbonate (0.129 g, 0.396 mmol) and pyrrolidine(71 μL, 0.85 mmol). The reaction mixture was heated at 100° C. foreighteen hours, cooled to room temperature, filtered over celite and thecelite pad was washed with ethyl acetate (30 mL). The filtrate wasconcentrated under reduced pressure and purified by flash columnchromatography using hexane-ethyl acetate (2:3) as the eluent to yieldthe title compound as an oil (0.04 g, 36.5%). ¹H NMR (CDCl₃): δ 8.6 (s,1H), 8.0 (s, 1H), 7.7 (s, 1H), 7.5 (s, 1H), 7.2-7.4 (m, 4H), 6.8 (d,1H), 5.5 (s, 2H), 4.1 (s, 3H), 3.6 (s, 3H), 3.4 (m, 4H), 2.1 (m, 4H).

Example 3 Part C7-Methoxy-2-[3-(1-pyrrolidinyl)phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0543] To a solution of 3B (0.04 g, 0.1 mmol) in dichloromethane (1 mL)was added five drops of 4N HCl in dioxane. The reaction mixture washeated at 45° C. for thirty minutes, concentrated under reduced pressureand kept on the high vacuum pump for thirty minutes to yield the titlecompound as a solid (0.038 g). ¹H NMR (CDCl₃): δ 8.6 (s, 1H), 8.5 (s,1H), 8.1 (s, 1H), 7.8 (s, 1H), 7.5 (t, 2H), 7.3 (s, 1H), 7.1 (m, 2H),6.8 (d, 2H), 4.1 (s, 3H), 3.4 (m, 4H), 2.0 (m, 4H). LC/MS (retentiontime=3.56 min.; M⁺ 388.15. Column: YMC ODS-A S5 C18 4.6×50 mm (4 min.gradient. Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; Solvent B=90% MeOH, 10%H₂O, 0.1% TFA).

EXAMPLE 4 7-Methoxy-2-(4-methylphenyl)-6-(5-oxazolyl)-4(1H)-quinolinone

[0544]

Example 4, Part A 5-(4-Amino-5-iodo-2-methoxyphenyl)oxazole

[0545]

[0546] To a solution of 1D (1.0 g, 5.26 mmol) in CH₂Cl₂ in a roundbottom flask was placed in an ice water bath. Pyridine (0.44 ml, 5.44mmol), iodine (1.38 g, 5.42 mmol) and AgSO₃CF₃ (1.39 g, 5.43 mmol) wereadded to the reaction mixture, which was stirred overnight at roomtemperature. The solid was removed with filtration and the solution waswashed with two 30 ml potions of water, 30 ml of NaHSO₃, 30 ml of water,30 ml of Brine, dried over Na₂SO₄. Filtration and removal of solventafforded the title compound (1.20 g, 72%). NMR (CD₃OD): □ 8.16 (1H, s),7.94 (1H, s), 7.32 (1H, 2), 6.60 (1H, s), 3.95 (3H, s); HPLC: 98%;LC-MS: m/z 317.04 (M+H)+

Example 4, Part A7-Methoxy-2-(4-methylphenyl)-6-(5-oxazolyl)-4(1H)-quinolinone

[0547] A small stainless steel bomb was charged with 4A, (100 mg, 0.3mmmol) dissolved in 2.5 ml of diethylamine. Hereto was addedp-methyl-phenylacetylene (81.7 μL, 0.6 mmol) and PdCl₂(PPh₃)₂ (19 mg,5%). The stainless steel bomb was sealed and charged with carbonmonoxide. The reaction was stirred for 4 hours at 119° C. with aninternal pressure of ˜40 psi. The reaction was cooled to roomtemperature and the reaction mixture transferred to a round bottom flaskby dissolving it in methylene chloride. The mixture was evaporated invacuo and the residue washed with warm methanol, and filtered. Thefiltrate was passed through a cation exchange plug, and the solvent wasremoved in vacuo to afford 25.4 mg of the desired product MW 332.36,yield 25.4%. The HPLC retention Time was 2.957 min (YMC S5 ODS 4.6×50 mmBallistic; Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH,10% H₂O, 0.2% H₃PO₄) with a LC/MS [M+H]⁺333.

EXAMPLE 53-[1,4-Dihydro-7-methoxy-6-(5-oxazaolyl)-4-oxo-2-quinolinyl]benzeneaceticAcid

[0548]

Example 5, Part A 3-Bromophenylacetic Acid Methyl Ester

[0549]

[0550] To a solution of 3-bromophenylacetic acid (1.0 g, 4.65 mmol),1,3-dicyclohexylcarbodiimide (1.44 g, 6.98 mmol) and MeOH (149 mg, 4.65mmol) in dichloromethane (40 ml) was added 4-dimethylaminopyridine (57mg, 0.465 mmol). The reaction mixture was stirred at RT for 1 hr. Thewhite solid was precipitated out which was removed with filtration. Thereaction solution was concentrated to give a crude product which waspurified on silica gel column with dichloromethane. The product wascollected which contain a little amount of DCU (1.36 g). NMR (CDCl₃): □7.20-7.46 (4H, m), 3.72 (3H, s), 3.621(2H, s).

Example 5, Part B 3-(Trimethylsilylethynly)phenylacetic Acid MethylEster

[0551]

[0552] A mixture of 5A (1.36 g, 5.52 mmol), (trimethylsilyl)acetylene(0.90 g, 9.15 mmol), bis(triphenylphosphine)palladium(II) acetate (0.40g, 0.539 mmol) and triethylamine (20 ml) in toluene (20 ml) was heatedto 90-100° C. for 2 hrs. The catalyst was removed with filtration. Thereaction mixture was concentrated to give a crude product which wasdissolved in 150 ml of EtOAc. It was washed with 50 ml of NaHCO₃, 50 mlof brine, dried over Na₂SO₄. Filtration and removal of solvent affordeda crude product which was purified by flash chromatography (silica,Hexane/CH₂Cl₂ 20/1) to give the title compound (0.88 g, 65%). NMR(CDCl₃): □ 6.96-7.22 (4H, m), 3.47 (3H, d, J=5.5 Hz), 3.37 (2H, d, J=2.9Hz).

Example 5, Part C 3-Ethynlyphenylacetic Acid

[0553]

[0554] A solution of 5B (0.88 g, 3.84 mmol) in THF (40 mL) was treatedwith Bu₄NF (4.5 mL 1M in THF) at ice water bath. The reaction mixturewas warmed up to RT and stirred for 20 minutes which was concentrated toyield a crude product. It was dissolved in 150 ml of ethyl acetate waswashed with 50 ml of water, 50 ml of brine, dried over K₂COs. Filtrationand removal of solvent afforded a crude product which was dissolved inMeOH (40 ml) and water (15 mL). To this solution was added LiOH*H₂O (200mg, 4.76 mmol) and stirred at RT for 1 hr. Filtration and removal ofsolvent afforded a crude product which was added water (50 ml). It wasacidified with 1N HCl solution until PH<3. The water phase was extractedwith three 50 ml portions of dichloromethane. The combined organic phasewas washed with water (50 ml), brine (50 ml) and then dried over MgSO₄.Filtration and removal of solvent afforded a crude product which waspurified by flash chromatography (silica, CH₂Cl₂/MeOH 20/1) to give thetitle compound (0.474 g, 77%). NMR (CDCl₃): □ 7.08-7.34 (4H, m), 3.52(1H, s), 3.51 (2H, d).

Example 5, Part D3-[1,4-Dihydro-7-methoxy-6-(5-oxazaolyl)-4-oxo-2-quinolinyl]benzeneaceticAcid

[0555] A mixture of above 5C (96 mg, 0.6 mmol), 4A (100 mg, 0.3 mmol),diethylamine (2.5 ml) and bis(triphenylphosphine)palladium(II) chloride(13 mg, 0.019 mmol) in a stainless steel pressure reaction vessel wasassembled and hooked up to a carbon monoxide tank. It was charged COabout 40 psi and heated to 120° C. for 20 minutes. The reaction mixturewas added MeOH (20 ml). Filtration and removal of solvent afforded acrude product which was purified by flash prep-TLC plate (silica, 25%methanol in CH₂Cl₂) to give the title compound (36 mg, 32%). NMR(CD₃OD): □ 8.67 (1H, s), 8.34 (1H, s), 7.76 (1H, 2), 7.58-7.66 (2H, m),7.44-7.55 (2H, m), 7.33 (1H, s), 6.57 (1H, s), 4.15 (3H, s), 3.61 (2H,s); HPLC: 96.9%; LC-MS: m/z 377.12 (M+H)+

EXAMPLE 63-[1,4-Dihydro-7-methoxy-6-(5-oxazaolyl)-4-oxo-2-quinolinyl]benzoic AcidMethyl Ester

[0556]

Example 6 Part A 3-(3-methoxycarbonylphenyl)-3-oxopropanoic Acid EthylEster

[0557]

[0558] Monomethyl isophathalate (2.0 g, 11.1 mmol) was dissolved in a1:3 mixture of tetrahydrofuran and dichloromethane. Carbonyldiimidazole(1.89 g, 11.7 mmol) was added slowly. The mixture was then stirred undernitrogen for 1 hr at room temperature. In a separate flask, ethylmalonate, potassium salt (3.96 g, 23.3 mmol) was dissolved inacetonitrile and magnesium chloride (2.64 g, 27.8 mmol) andtriethylamine (4.95 ml, 35.5 mmol) was added to result in aheterogeneous suspension, which was stirred at room temperature for 1 h.The two reaction mixtures were mixed, and the resulting suspension wasstirred @80° C. for 8 hours. 100 ml of a 2N aqueous HCl solution wasadded to the reaction mixture, which was subsequently extracted withdichloromethane. The organic layer was washed with 2N HCl twice andtwice with water, dried (MgSO₄) and evaporated in vacuo to afford 4.0 gof an oil. Purification on silica gel using Biotage® eluting with 20%EtOAc in Hexanes, recovered 1.5 g of 6A as a clear oil. LC/MS: RetentionTime=1.38 min (YMC S5 Turbopack 4.6×33 mm, 2 min gradient; Solvent A=10%MeOH, 90% H₂O, 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, 0.1% TFA) with a(M+H)⁺=251.13. ¹H-NMR (Joel 500 Hz/CDCl₃) (1:2 mixture of enol and ketoform) Keto: δ 1.17-1.21 (t, 3H, J=8.8 Hz), 3.89 (s, 3H), 3.96 (s, 2H),4.12-4.18 (q, 2H, J=8.8 Hz) 5.67(s, 1H); 7.50-7.54 (t, 1H, J=9.3 Hz),8.07-8.09 (d, 1H, J=9.9 Hz), 8.19-8.21 (d, 1H, J=9.9 Hz), 8.5 (d,1H,J=2.2 Hz)

Example 6 Part B 3-(3-Methoxycarbonylphenyl)-3-(methylamino)-2-propenoicAcid Ethyl Ester

[0559]

[0560] A mixture of 6A (0.730 g, 2.92 mmol), methylamine (7.29 mL, 14.6mmol of a 2.0 M solution in methanol), and acetic acid (0.84 mL, 14.6mmol) in 14 mL of ethanol was heated a approximately 80° overnight. Thesolvent was removed under reduced pressure, and the residue wasdissolved in dichloromethane and washed three times with a saturatedaqueous brine solution. The organic layer was dried over anhydroussodium sulfate and concentrated to give 0.766 g (99%) of 6B. ¹H-NMR (400mHz, CDCl₃) □ 1.26-1.30 (m, 3H), 2.75-2.77 (m, 2H), 3.94 (s, 3H),4.12-4.18 (m, 2H), 4.60 (s, 1H), 7.49 (t, 1H, J=7.6 Hz), 7.55 (d, 1H,J=7.6 Hz), 8.04 (s, 1H), 8.08 (d, 1H, J=7.6 Hz), and 8.48 (brs, 1H)

Example 6, Part C3-[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-(3-methoxycarbonylphenyl)-2-propenoicAcid Ethyl Ester

[0561]

[0562] A mixture of the 1D (0.496 g, 2.61 mmol), 6B (0.756 g, 2.87mmol), and pyridinium p-toluenesulfonate (0.722 g, 2.87 mmol) in 22 mLof dry dichloromethane was heated at reflux overnight. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure and purified by silica gel chromatography to give 0.783 g (71%)of the 6C as a pale yellow semi-solid. The product had an analyticalHPLC retention time=3.92 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic;Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O,0.2% H₃PO₄) and a LC/MS (M+1)⁺423.26.

Example 6, Part D3-[1,4-Dihydro-7-methoxy-6-(5-oxazaolyl)-4-oxo-2-quinolinyl]benzoic AcidMethyl Ester

[0563] A solution of 6C (0.783 g, 1.85 mmol) in approximately 10 mL ofxylene was divided between two sealed tubes. The reaction mixtures wereheated at 250° C. overnight. The resulting precipitate was collected viavacuum filtration to give 0.334 g (48%) of the 6 as a white solid. Thefiltrate was concentrated to provide recovered 6C along with someadditional quinolone 6. The product was 100% pure by analytical HPLCwith a retention time=2.92 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic;Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O,0.2% H₃PO₄) and a LC/MS M⁺¹=377.28. ¹H-NMR (400 mHz, DMSO) □ 3.93 (s,3H), 4.06 (s, 3H), 6.37 (s, 1H), 7.39 (s, 1H), 7.61 (s, 1H), 7.73-7.77(m, 1H), 8.12-8.16 (m, 2H), 8.41 (s, 2H), 8.49 (s, 1H), and 11.85 (s,1H).

EXAMPLE 72-[3-(Hydroxymethyl)phenyl]-7-methoxy-6-(5-oxazaolyl)-4(1H)-quinolinone

[0564]

[0565] To 6 (0.100 g, 0.266 mmol) in 20 mL of anhydrous tetrahydrofuranand 20 mL of 1,4-dioxane was added lithium aluminum hydride (0.80 mL ofa 1.0 M solution in tetrahydrofuran, 0.798 mmol) at room temperature.The reaction mixture was stirred for 1 h. To the mixture was added water(31.0 □L), followed by 15% aqueous sodium hydroxide (31.0 □L), andfinally, additional water (93.0 □L). The mixture was stirred for 1 h.The solvent was removed under reduced pressure, and the residue waspurified by silica gel chromatography to give 85 mg (91%) of the productas an off-white solid. The product was 100% pure by analytical HPLC witha retention time=2.52 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic;Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O,0.2% H₃PO₄) and a LC/MS M⁺¹=349.16.

EXAMPLE 82-[3-(1-Hydroxy-1-methylethyl)phenyl]-7-methoxy-6-(5-oxazaolyl)-4(1H)-quinolinone

[0566]

[0567] To 6 (0.015 g, 0.040 mmol) in 14 mL of anhydrous tetrahydrofuranat room temperature was added methyl magnesium bromide (80.0 mL of a 3.0M solution in tetrahydrofuran, 0.239 mmol). The reaction mixture wasstirred for 30 min. and then quenched with a small amount of a saturatedaqueous solution of ammonium chloride. The mixture was filtered, and thesolvent was removed under reduced pressure. The resulting crude productwas purified by preparative HPLC to afford 6.0 mg of the product as aoff-white solid. The product was 96% pure by analytical HPLC with aretention time=2.77 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic;Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O,0.2% H₃PO₄) and a LC/MS M⁺¹=377.22.

EXAMPLE 97-Methoxy-2-[3-(4-methyl-1-piperazinyl)phenyl]-6-(5-oxazaolyl)-4(1H)-quinolinone

[0568]

Example 9, Part A2-[3-(4-methyl-1-piperazinyl)phenyl]-7-methoxy-4-methoxymethoxy-6-(5-oxazolyl)quinoline

[0569]

[0570] 9A was prepared from 3A by a route analogous to that used for thepreparation of 3B, except in the purification step: the reaction mixturewas concentrated in vacuo and carried to the next step without furtherpurification.

Example 9, Part B7-Methoxy-2-[3-(4-methyl-1-piperazinyl)phenyl]-6-(5-oxazaolyl)-4(1H)-quinolinone

[0571] To a solution of crude 9A (43 mg, 0.098 mmol) in dichloromethane(0.4 mL) was added 1 mL TFA dropwise and stirred at room temperature for30 minutes. The reaction mixture was then concentrated in vacuo andsubject to preparative HPLC (Preparative HPLC Conditions: YMC S5 ODS20×100 mm column, start %B=0, final %B=100, gradient time=10 min,wavelength=254, solvent A=10% MeOH, 90% H₂O, 0.1% TFA, solvent B=90%MeOH, 10% H₂O, 0.1% TFA). to give 12 mg of 9 as yellow solid (TFA salt).LC/MS (retention time=2.393 min.; M⁺ 417. Column: YMC ODS-A S5 C184.6×50 mm (4 min. gradient. Solvent A=10% MeOH, 90% H₂O, 0.1% TFA;Solvent B=90% MeOH, 10% H₂O, 0.1% TFA).

EXAMPLE 102-[2,3-Dihydro-3-(dimethylamino)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0572]

Example 10 Part A, 6-Bromo-2,3-dihydro-1H-inden-1-ol

[0573]

[0574] To a solution of 6-bromo-1-indanone (prepared as described byCornelius, Lyndon A. M. and Combs, Donald W. Synth. Commun. (1994),24(19), 2777-88) (1.4 g, 6.57 mmol) in 20 mL of methanol was addedsodium borohydride (0.087 g, 2.3 mmol) over a period of five minutes atroom temperature. The reaction mixture was stirred for two hours at roomtemperature, concentrated under pressure and partitioned between ethylacetate (50 mL) and 1N HCl (20 mL). The ethyl acetate layer was driedover sodium sulfate and concentrated under reduced pressure to yield thetitle compound as a solid (1.4 g, 99%). ¹H NMR (CDCl₃): δ 7.45 (s, 1H),7.3 (d, 1H), 7.0 (d, 1H), 5.2 (t, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.4 (m,1H), 1.9 (m, 2H).

Example 10 Part B 6-Bromo-1-(dimethylamino)-2,3-dihydro-1H-indene

[0575]

[0576] To a solution of 10A (0.767 g, 3.56 mmol) in anhydrous toluene(10 mL) was added thionyl chloride (0.4 mL, 5.34 mmol) at roomtemperature. The reaction mixture was stirred at room temperature fortwenty minutes and heated at 50° C. for one hour. The reaction mixturewas concentrated under reduced pressure and partitioned betweendichloromethane (20 mL) and water (20 mL). The dichloromethane layer isdried over sodium sulfate and concentrated under reduced pressure toyield a liquid (0.641 g), which was used as such for the subsequent stepwithout further purification.

[0577] To the liquid obtained above (0.641 g) was added dimethylamine (2mL of a 33% solution in ethyl alcohol) and the contents were heated in asealed tube at 90° C. for eighteen hours. The reaction mixture wascooled to room temperature, concentrated under reduced pressure andpurified by flash column chromatography using dichloromethane-methanol(18:1) as the eluent to yield the title compound as an oil (0.362 g, 42%over two steps). ¹H NMR (CDCl₃): δ 7.45 (s, 1H), 7.3 (d, 1H), 7.0 (d,1H), 4.2 (t, 1H), 2.9 (m, 1H), 2.8 (m, 1H), 2.2 (s, 6H), 1.95 (m, 2H).

Example 10, Part C,1-(Dimethylamino)-2,3-dihydro-6-[(trimethylsilyl)ethynyl]-1H-indene

[0578]

[0579] To 10B (0.29 g, 1.21 mmol), under a nitrogen atmosphere wassequentially added triethylamine (0.37 mL, 2.66 mmol), copper(I)iodide(0.018 g, 0.0968 mmol), bis(triphenylphosphine)palladium(II)dichloride(0.034 g, 0.0484 mmol) and trimethylsilyl acetylene (0.2 mL, 1.45 mmol).The reaction mixture was heated at 80° C. for two hours. The reactionmixture was cooled to room temperature, dichloromethane (20 mL) wasadded and the contents filtered over a thin pad of celite. The filtrateis concentrated under reduced pressure and purified by flash columnchromatography using dichloromethane-methanol (18:1) as the eluent toyield the title compound as an oil (0.300 g, 96%). ¹H NMR (CDCl₃): δ 7.5(s, 1H), 7.3 (d, 1H), 7.1 (d, 1H), 4.3 (t, 1H), 2.9 (m, 1H), 2.8 (m,1H), 2.2 (s, 6H), 2.1 (m, 2H), 0.2 (s, 9H).

Example 10, Part D 1-(Dimethylamino)-6-ethynyl-2,3-dihydro-1H-indene

[0580]

[0581] To a solution of XC (0.3 g, 1.16 mmol) in anhydrous THF (5 mL)was added tetrabutylammonium fluoride (1.4 mL, 1.39 mmol of a 1.0Msolution in THF) at room temperature. The reaction mixture was stirredat room temperature for two hours, concentrated under reduced pressureand purified by flash column chromatography usingdichloromethane-methanol (18:1) as the eluent to yield the titlecompound as an oil (0.18 g, 83%). ¹H NMR (CDCl₃): δ 7.45 (s, 1H), 7.3(d, 1H), 7.1 (d, 1H), 4.2 (t, 1H), 2.95 (s, 1H), 2.9 (m, 1H), 2.8 (m,1H), 2.2 (s, 6H), 2.0 (m, 2H).

Example 10, Part E2-[2,3-Dihydro-3-(dimethylamino)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0582]

[0583] 4A 0.15 g (0.47 mmol), 0.18 g (0.94 mmol) of 10D, 0.02 g (0.028mmol) of bis(triphenylphosphine)palladium(II)dichloride and diethylamine(5 mL) were reacted in a similar manner to Example 5, part D. Thereaction was conducted at 120° C. for 30 minutes and then cooled to roomtemperature. Methanol (60 mL) was added and the contents filtered. Theresidue was concentrated under reduced pressure and purified by flashcolumn chromatography using dichloromethane-methanol (7:3) as the eluentto yield the title compound as a solid (0.135 g, 71%). LC/MS (retentiontime=2.31 min.; M⁺ 402.24. Column: YMC ODSA 5u C18 4.6×50 mm (4 min.gradient. Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; Solvent B=90% MeOH, 10%H₂O, 0.1% TFA).

EXAMPLE 112-(2,3-Dihydro-3-methoxy-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0584]

Example 11, Part A 6-Bromo-2,3-dihydro-1-methoxy-1H-indene

[0585]

[0586] To a solution of 10A (0.51 g, 2.4 mmol) in 10 mL of anhydrous THFwas added sodium hydride (0.097 g, 3.84 mmol) over a period of 5 minutesat room temperature. After stirring the reaction mixture for fifteenminutes at room temperature, methyl iodide (0.22 mL, 3.6 mmol) was addedand the contents stirred at room temperature for thirty minutes. Thereaction mixture was concentrated and partitioned between ethyl acetate(20 mL) and water (20 mL). The ethyl acetate layer was washed with 1NHCl (20 mL), brine (20 mL), dried over sodium sulfate and concentratedto yield the title compound as a liquid (0.485 g, 89%). ¹H NMR (CDCl₃) δ7.45 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 4.7 (m, 1H), 3.3 (s, 3H), 2.9(m, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H).

Example 11, Part B2,3-Dihydro-1-methoxy-6-[(trimethylsilyl)ethynyl]-1H-indene

[0587]

[0588] 11A 0.485 g (2.14 mmol), 0.36 mL (2.56 mmol) of trimethylsilylacetylene, 0.06 g (0.085 mmol) ofbis(triphenylphosphine)palladium(II)dichloride, 0.032 g (0.171 mmol) ofcopper(I)iodide and 0.65 mL (4.7 mmol) of triethylamine were reacted ina similar manner to Example 10, part C, to yield the title compound asan oil (0.5 g, 96%). ¹H NMR (CDCl₃): δ 7.3 (s, 1H), 7.2 (d, 1H), 7.0 (d,1H), 4.6 (m, 1H), 3.2 (s, 3H), 2.9 (m, 1H), 2.6 (m, 1H), 2.2 (m, 1H),1.95 (m, 1H). 0.1 (s, 3H).

Example 11, Part C 6-Ethynyl-2,3-dihydro-1-methoxy-1H-indene

[0589]

[0590] 11B, 0.5 g (2.05 mmol) and 2.46 mL (2.46 mmol of 1.0M solution inTHF) of tetrabutylammonium flouride were reacted in a similar manner toexample 10, part D, to yield the title compound as an oil (0.5 g, 99%).¹H NMR (CDCl₃): δ 7.45 (s, 1H), 7.3 (d, 1H), 7.1 (d, 1H), 4.8 (m, 1H),3.3 (s, 3H), 3.0 (m, 2H), 2.75 (m, 1H), 2.25 (m, 1H), 2.0 (m, 1H).

Example 11, Part D2-(2,3-Dihydro-3-methoxy-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0591] 4A , 0.15 g (0.47 mmol), 0.163 g (0.94 mmol) of 1D, 0.02 g (0.028mmol) of bis(triphenylphosphine)palladium(II)dichloride and diethylamine(5 mL) were reacted in a similar manner were reacted in a similar mannerto Example 5, part D to yield the title compound as a solid (0.04 g,21%). ¹H NMR (CDCl₃): δ 11.8 (s, 1H), 8.5 (s, 1H), 8.4 (s, 1H), 7.8 (s,1H), 7.75 (d, 1H), 7.6 (s, 1H), 7.4 (d, 1H), 7.35 (s, 1H), 6.3 (s, 1H),4.9 (m, 1H), 4.1 (s, 3H), 3.3 (s, 3H), 3.0 (m, 1H), 2.85 (m, 1H), 2.4(m, 1H), 2.0 (m,1H).

EXAMPLES 12 to 103

[0592] Examples 12 to 103 are prepared by several routes. The method toprepare a specific example is noted in table 1. Examples prepared in amanner analogous to Example 1 starting with aniline 1D and anappropriate beta-ketoester are designated as method A1. Examplesprepared in a manner analogous to Example 2 starting with aniline 1D anda appropriate beta-ketoester, which may be obtained from commerciallyavailable acid chlorides, are designated as method A2. Example preparedfrom esters, which are readily converted to an acid by hydrolysis, oracids, followed by reaction of the acid with carbonyldiimidazole, andreacted with potassium ethyl malonate as described in Example 6, part A,are designated as method A3. Examples which starting with intermediate3A, and react in a manner analogous to example 3, are designated asmethod B1. Compounds prepared in a manner analogous to Example 9 aredesignated as method B2 Examples which starting with intermediate 4A,and react it with a commercially available terminal alkyne, prepared ina manner analogous to example 4, are designated as method C1. Exampleswhich starting with intermediate 4A, and react it with a terminalalkyne, which is prepared from a commercially available aryl halide andtrimethylsilylacetylene as described in Example 5, Part B and Part C,and then reacted to form a quinolone in a manner analogous to example 4,are designated as method C2. Compounds prepared in a manner analogous toExample 7 are designated as method D1. Compounds prepared in a manneranalogous to Example 8 are designated as method D2. The compounds ofthese examples have structures outlined in Table 1 below.

[0593] Column conditions A: YMC ODSA S5 C18 4.6×50 mm (4 min. gradient.Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, 0.1%TFA).

[0594] Column conditions B: Column: YMC S5 Turbopack Pro 4.6×33 mm (2min. gradient. Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; Solvent B=90%MeOH, 10% H₂O, 0.1% TFA).

[0595] Column conditions C: YMC ODSA 5μ C18 4.6×50 mm (4 min. gradient.Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, 0.1%TFA).

[0596] Column conditions D: YMC S5 CombiScreen 4.6×50 mm; Gradient time:4 min; Flow rate=4 ml/min; Solvent A=10% MeOH, 90% Water, 0.2% H₃PO₄;Solvent B=90% MeOH, 10% water, 0.2% H₃PO₄ Start % B=0; Final % B=100;

[0597] Column conditions E: YMC S5 ODS 4.6×50 mm; Gradient time: 4 min;Flow rate=4 ml/min; Solvent A=10% MeOH, 90% Water, 0.2% H₃PO₄; SolventB=90% MeOH, 10% water, 0.2% H₃PO₄ Start % B=0; Final % B=100;

[0598] Column condition F: YMC PRO S5 4.6×33 mm; Gradient time: 2 min;Flow rate=4 mL/min; Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; Solvent B=90%MeOH, 10% H₂O, 0.1% Start % B 0; Final % B=100. TABLE 1

HPLC Condi- tions/ EX. Compound Meth- time No R¹ R³ Name od (min.) M +H⁺ 12

H 7-Methoxy-2-(3- furanyl)-6-(5- oxazolyl)-4(1H)- quinolinone A1 E/3.10299.22 13

H 7-Methoxy-2-(3- methylphenyl)-6- (5-oxazolyl)- 4(1H)-quinolinone C1E/3.55 333.16 14

H 2-(2- Fluorophenyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone A1E/2.73 337.16 15 Me H 7-Methoxy-2- A1 E/2.00 257.14 methyl-6-(5-oxazolyl)-4(1H)- quinolinone 16

Me 7-Methoxy-3- methyl-6-(5- oxazolyl)-2- phenyl-4(1H)- quinolinone A1E/2.98 333.09 17

H 7-Methoxy-6-(5- oxazolyl)-2-(2- pyrrolidinyl)- 4(1H)-quinolinone A1A/1.86 312.20 18

H 2-[1,4-Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]-1-pyrrolidinecarboxylic acid phenylmethyl ester A1 A/2.71 446.14 19

H N-[3-[1,4- Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]phenyl]-2- hydroxy-N- methylacetamide C2 D/2.44 448.14 20

H 2-(Acetyloxy)-N- [3-[1,4-dihydro- 7-methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]phenyl]- N-methylacetamide C2 D/2.64 406.12 21

H N-[3-[1,4- Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]phenyl]- N-methyl-4- morpholineacetamide C2 D/1.97 475.42 22

H 4-[1,4-Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2- quinolinyl]benzoicacid methyl ester A2 E/2.95 377.20 23

H 7-Methoxy-2-(4- methoxyphenyl)-6- (5-oxazolyl)- 4(1H)-quinolinone A1E/2.80 349.18 24

H 7-Methoxy-6-(5- oxazolyl)-2-(3- pyridinyl)-4(1H)- quinolinone A1E/2.12 320.13 25

H N,N-Diethyl-1,4- dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinepropamide C1 D/2.42 370.38 26

H 7-Methoxy-6-(5- oxazolyl)-2- (phenylmethyl)- 4(1H)-quinolinone A2E/2.68 333.16 27

H 2-(4- Hydroxyphenyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone A22.69 335.12 28

H 2-(3,4- Dimethylphenyl)- 7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinoneA3 E/3.17 347.19 29

H 4-[1,4-Dihydro-7- methoxy-6-(4- oxazolyl)-4-oxo- 2-quinolinyl]benzene- butanoic acid methyl ester C2 D/3.17 419.1 30

H 4-[1,4-Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]benzene- butanoic acid C2 D/2.94 405.11 31

H 4-[1,4-Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]benzene- acetic acid C2 D/2.65 377.14 32

H 7-Methoxy-6-(5- oxazolyl)-2-(3- thienyl)-4(1H)- quinolinone A1 A/2.88325.10 33

H 7-Methoxy-6-(5- oxazolyl)-2-(2- thienyl)-4(1H)- quinolinone A1 C/2.72325.05 34

H 7-Methoxy-2-[3- (4- morpholinyl)phenyl]- 6-(5- oxazolyl)-4(1H)-quinolinone B1 B/1.43 404.22 35

H 7-Methoxy-2-(2- methylphenyl)-6- (5-oxazolyl)- 4(1H)-quinolinone A3C/2.76 333.10 36

H 7-Methoxy-2-[3- (1- piperidinyl)phenyl]- 6-(5- oxazolyl)-4(1H)-quinolinone B1 A/2.32 402.36 37

H 2-[3- [(Dimethylamino)meth- yl]phenyl]-7- methoxy-6-(5-oxazolyl)-4(1H)- quinolinone A3 C/2.20 376.19 38

Br 3-Bromo-2-[3- [(dimethylamino)meth- yl]phenyl]-7- methoxy-6-(5-oxazolyl)-4(1H)- quinolinone A3 A/2.24 456.25 39

H 3-[1,4-Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]benzene- propanoic acid C2 D/2.82 391.13 40

H 2-(2- Hydroxyethyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone C1D/1.75 287.13 41

H 2- [(Dimethylamino)meth- yl]-7-methoxy- 6-(5-oxazolyl)-4(1H)-quinolinone C1 D/1.18 300.16 42

H 2-(3- Hydroxypropyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone C1D/1.94 301.15 43

H 2-(4- Hydroxybutyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone C1D/2.06 315.16 44

H 2- (Hydroxymethyl)- 7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinone C1D/1.75 273.1 45

H 7-Methoxy-2- (methoxymethyl)- 6-(5-oxazolyl)- 4(1H)-quinolinone C1D/2.09 287.12 46

H 2-(2- Hydroxypropyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone C1D/1.90 301.17 47

H 2-[3-(1-Hydroxy- 1- methylethyl)phenyl]- 7-methoxy-6- (5-oxazolyl)-4(1H)-quinolinone A3 E/2.77 377.22 48

H 4-[1,4-Dihydro- 7-methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]benzene- sulfonamide A3 E/2.35 398.16 49

H 2- (Hydroxyphenylmeth- yl)-7-methoxy-6- (5-oxazolyl)-4(1H)-quinolinone C1 D/3.31 349.24 50

H 2-(1- Hydroxyethyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone C1D/2.08 273.16 51

H 7-Methoxy-6-(5- oxazolyl)-2-(4- pyridinyl)-4(1H)- quinolinone A3E/2.00 320.12 52

H 7-Methoxy-2-[3- [(3S)-3-methyl-1- piperazinyl]phenyl]- 6-(5-oxazolyl)-4(1H)- quinolinone B2 D/2.833 417 53

H 7-Methoxy-2-[3- (4- morpholinylmeth- yl)phenyl]-6-(5- oxazolyl)-4(1H)-quinolinone A3 1.92 418.20 54

H 2-[4-(1-Hydroxy- 1- methylethyl)phenyl]- 7-methoxy-6- (5-oxazolyl)-4(1H)-quinolinone D2 2.70 377.28 55

H 2-[4- (Hydroxymethyl)phen- yl]-7-methoxy- 6-(5-oxazolyl)-4(1H)-quinolinone D1 2.45 349.23 56

H 7-Methoxy-2-[3- [(4- methoxyphenyl)meth- oxy]phenyl]-6- (5-oxazolyl)-4(1H)-quinolinone A3 E/3.54 455.10 57

H 2-(3- Hydroxyphenyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone A3E/2.76 355.10 58

H 2-[3-[2- (Dimethylamino)eth- oxy]phenyl]-7- methoxy-6-(5-oxazolyl)-4(1H)- quinolinone A3 E/2.28 406.37 59

H 2-(2,3-Dihydro-1- methyl-1H- isoindol-5-yl)-7- methoxy-6-(5-oxazolyl)-4(1H)- quinolinone C2 E/2.18 374.16 60

H 7-Methoxy-6-(5- oxazolyl)-2-(4- thiazolyl)-4(1H)- quinolinone A3E/2.67 326.05 61

H 7-Methoxy-6-(5- oxazolyl)-2-[2- (1-piperidinyl)- 4-thiazolyl]-4(1H)-quinolinone C2 E/3.49 409.10 62

H 2-(3,5- Dimethylphenyl)- 7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinoneC2 E/3.36 347.15 63

H 7-Methoxy-2-[3- (methylthio)phenyl]- 6-(5- oxazolyl)-4(1H)-quinolinone C2 E/3.29 365.08 64

H 7-Methoxy-2-[3- (methylsulfonyl)phen- yl]-6-(5- oxazolyl)-4(1H)-quinolinone C2 E/2.47 397.07 65

H 7-Methoxy-2-[3- [4-(2- methoxyethyl)-1- piperazinyl]phen- yl]-6-(5-oxazolyl)-4(1H)- quinolinone B2 A/2.42 461.54 66

H 2-[3-(2,6- Dimethyl-4- morpholinyl)phen- yl]-7-methoxy-6-(5-oxazolyl)- 4(1H)-quinolinone B2 A/3.11 432.23 67

H 2-(3-Bromo-4- methylphenyl)-7- methoxy-6-(5- oxazolyl)-4(1H)-quinolinone A1 A/3.31 411.08 68

H 7-Methoxy-6-(5- oxazolyl)-2-[3- [[(tetrahydro-2- furanyl)methyl]a-mino]phenyl]- 4(1H)-quinolinone B2 A/2.91 418.23 69

H 2-[3-[3- (Dimethylamino)- 1- pyrrolidinyl]phen- yl]-7-methoxy-6-(5-oxazolyl)- 4(1H)-quinolinone B2 A/2.46 431.25 70

H 2-[3-[3- (Dimethylamino)- 1- pyrrolidinyl]phen- yl]-7-methoxy-6-(5-oxazolyl)- 4(1H)-quinolinone B2 A/3.07 418.21 71

H 7-Methoxy-2-[4- methyl-3-(4- methyl-1- piperazinyl)phen- yl]-6-(5-oxazolyl)-4(1H)- quinolinone B2 A/2.54 431.25 72

H 4-[5-[1,4- Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]-2-methylphenyl]-1- piperzazinecarboxy- lic acid 1,1- dimethylethyl esterB2 A/3.57 517.29 73

H 7-Methoxy-2-[4- methyl-3-(1- pyrrolidinyl)phen- yl]-6-(5-oxazolyl)-4(1H)- quinolinone B2 A/2.46 402.22 74

H 7-Methoxy-2-[3- [(2- methoxyethyl)a- mino]-4- methylphenyl]-6-(5-oxazolyl)- 4(1H)-quinolinone B2 A/2.93 406.22 75

H 4-[[5-[1,4- Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]-2-methylphenyl]a- mino]-1- piperidinecarboxy- lic acid ethyl ester B2A/3.18 503.27 76

H 2-[3-[(3R)-3- (Dimethylamino)- 1-pyrrolidinyl]- 4-methylphenyl]-7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinone B2 A/2.57 445.29 77

H 2-[2,3-Dihydro-3- (1-pyrrolidinyl)- 1H-inden-5-yl]-7- methoxy-6-(5-oxazolyl)-4(1H)- quinolinone B2 A/2.55 417.23 78

H 7-Methoxy-2-[4- methyl-3-(1- piperazinyl)phen- yl]-6-(5-oxazolyl)-4(1H)- quinolinone B2 A/3.37 434.19 79

H 2-(3-Bromo-4- methoxyphenyl)-7- methoxy-6-(5- oxazolyl)-4(1H)-quinolinone A1 B/1.66 429.06 80

H 2-[3-(1,1- Dioxido-4- thiomorpholinyl)- 4-methylphenyl]-7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinone B2 B/1.48 466.14 81

H 7-Methoxy-2-[4- methoxy-3-(4- morpholinyl)phen- yl]-6-(5-oxazolyl)-4(1H)- quinolinone B2 B/1.50 434.25 82

H 7-Methoxy-2-[4- methoxy-3-[(2R)- 2- (methoxymethyl)- 1-pyrrolidinyl]phen- yl]-6-(5- oxazolyl)-4(1H)- quinolinone B2 A/2.51462.53 83

H 2-[3-(1- Azetidinyl)-4- methoxyphenyl]-7- methoxy-6-(5-oxazolyl)-4(1H)- quinolinone B2 A/2.55 404.45 84

H 7-Methoxy-2-[4- methoxy-3-(4- methyl-1- piperazinyl)phen- yl]-6-(5-oxazolyl)-4(1H)- quinolinone B2 A/2.41 447.51 85

H 7-Methoxy-2-[4- methoxy-3-[[2- (methylamino)eth- yl]amino]phenyl]-6-(5-oxazolyl)- 4(1H)-quinolinone B2 A/2.50 421.48 86

H 2-[3-[(3R)-3- (Dimethylamino)- 1-pyrrolidinyl]- 4-methoxyphenyl]-7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinone B2 A/2.50 461.55 87

H 7-Methoxy-2-[4- methoxy-3-[(2- methoxyethyl)a- mino]phenyl]-6-(5-oxazolyl)-4(1H)- quinolinone B2 A/2.91 422.46 88

H 7-Methoxy-2-[4- methoxy-3-[[2-(4- morpholinyl)eth- yl]amino]phenyl]-6-(5-oxazolyl)- 4(1H)-quinolinone B2 A/2.50 477.57 89

H 5-[1,4-Dihydro-7- methoxy-6-(5- oxazolyl)-4-oxo- 2-quinolinyl]-2-methyl- benzonitrile B3 E/3.57 358.38 90

H 7-Methoxy-6-(5- oxazolyl)-2- (5,6,7,8- tetrahydro-8-oxo-2-naphthalenyl)- 4(1H)-quinolinone C3 A/2.95 387.10 91

H 7-Methoxy-6-(5- oxazolyl)-2- (5,6,7,8- tetrahydro-8- hydroxy-2-naphthalenyl)- 4(1H)-quinolinone D3 A/2.91 389.19 92

H Dimethylcarbamic acid 7-[1,4- dihydro-7- methoxy-6-(5-oxazolyl)-4-oxo- 2-quinolinyl]- 1,2,3,4- tetrahydro-1- naphthalenylester D3 A/3.34 460.41 93

H 2-[8- (Dimethylamino)- 5,6,7,8- tetrahydro-2- naphthalenyl]-7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinone D3 A/2.43 416.20 94

H 2-Ethyl-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone A1 E/1.33 271 95

H 7-Methoxy-6-(5- oxazolyl)-2-[3- (trifluoromethyl) phenyl]-4(1H)-quinolinone A1 E/3.18 387.21 96

H 7-Methoxy-6-(5- oxazolyl)-2-[4- (trifluoromethyl) phenyl]-4(1H)-quinolinone A1 E/3.16 387.22 97

H 2-[4- (Dimethylamino)- 3,4-dihydro-2H-1- benzopyran-6-yl]-7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinone C1 E/1.40 418.09 98

H 2-Cyclohexyl-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone C1 E/1.73271.1 99

H 2-[3,4-Dihydro-4- (1-pyrrolidinyl)- 2H-1-benzopyran- 6-yl]-7-methoxy-6-(5-oxazolyl)- 4(1H)-quinolinone C1 E/1.73 444.54 100

H 7-Methoxy-6-(5- oxazolyl)-2-(1- phenylcyclopropyl)- 4(1H)- quinolinoneC1 E/1.76 325.15 101

H 2-(4- Bromophenyl)-7- methoxy-6-(5- oxazolyl)-4(1H)- quinolinone A3D/3.24 397.11 102

H 7-Methoxy-2-[4- (4-methyl-1- piperazinyl)phenyl]- 6-(5-oxazolyl)-4(1H)- quinolinone C2 D/1.91 417.16 103

H 7-Methoxy-2-[4- (4- morpholinyl)phen- yl]-6-(5- oxazolyl)-4(1H)-quinolinone C2 D/2.84 404.15

EXAMPLE 104[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]methylcarbamicAcid Phenylmethyl Ester

[0599]

Example 104, Part A 6-Bromo-2,3-dihydro-N-methyl-1H-inden-1-amine

[0600]

[0601] To a solution of 6-bromoindanol (0.65 g, 3.02 mmol) in toluene(10 mL) was added thionyl chloride (0.34 mL, 4.53 mmol) and the contentsheated at 50° C. for one hour. The reaction mixture was cooled to roomtemperature and partitioned between dichloromethane (20 mL) and water(20 mL). The dichlromethane layer was dried over sodium sulfate andconcentrated under reduced pressure to yield a liquid (0.63 g) which wasused as such for the subsequent step without further purification.

[0602] To 6-bromo-1-chloroindane obtained in the previous step was addedmethylamine (6 mL of a 33% solution in ethanol) and the contents heatedin a sealed tube at 90° C. for eighteen hours. The reaction mixture wasconcentrated under reduced pressure and purified by silica gel flashchromatography using dichloromethane/methanol to yield the titlecompound (0.251 g, 37%). ¹H NMR (CDCl₃): □ 7.45 (s, 1H), 7.25 (d, 1H),7.0 (d, 1H), 4.1 (t, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.5 (brs, 1H), 2.4(s, 3H), 2.3 (m, 1H), 1.8 (m, 1H).

Example 104, Part B (6-Bromo-2,3-dihydro-1H-inden-1-yl)methylcarbamicAcid Phenylmethyl Ester

[0603]

[0604] To a solution of 104A (0.251 g, 1.11 mmol) in dioxane/water (10:5mL) was added sodium carbonate (0.294 g, 2.77 mmol) followed bybenzyloxycarbonyl chloride (0.19 mL, 1.33 mmol) at room temperature. Thereaction mixture was stirred at room temperature for one hour andpartitioned between ethyl acetate (2×20 mL) and water (20 mL). The ethylacetate layer is dried over sodium sulfate and concentrated underreduced pressure to yield the title compound (0.392 g, 98%). ¹H NMR(CDCl₃, mixture of rotomers): □ (7.3 m, 7H), 7.0 (m, 1H), 5.8, 5.7 (t,1H), 5.1 (s, 2H), 2.9 (s, 1H), 2.8 (s, 1H), 2.6, 2.55 (s, 3H), 2.3 (m,1H), 1.9 (m, 1H).

Example 104, Part C[2,3-Dihydro-6-[(trimethylsilyl)ethynyl]-1H-inden-1-yl]methylcarbamicAcid Phenylmethyl Ester

[0605]

[0606] A mixture of 104B (0.392 g, 1.08 mmol), (trimethylsilyl)acetylene(0.18 mL, 1.3 mmol), bis(triphenylphosphine)palladium(II) chloride(0.030 g, 0.04 mmol), copper(I)iodide (0.016 g, 0.08 mmol) andtriethylamine (0.33 mL, 2.4 mmol) in toluene was heated to 80° C. for 2hrs. The reaction mixture was filtered over celite. The filtrate wasconcentrated under reduced pressure and purified by silica gel flashchromatography employing dichloromethane/methanol to give the titlecompound (0.375 g, 91%). LC-MS: Column A, retention time=4.5 minutes,m/z 378.17 (M+H)⁺.

Example 104, Part D (6-Ethynyl-2,3-dihydro-1H-inden-1-yl)methylcarbamicAcid Phenylmethyl Ester

[0607]

[0608] Compound 104C (0.375 g, 0.99 mmol) was subjected to the sameconditions as outlined in C2 (example 4) to yield the title compound(0.285 g, 94%). LC-MS: Column A, retention time 3.86 minutes, m/z 306.14(M+H)⁺.

Example 104, Part F[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]methylcarbamicAcid Phenylmethyl Ester

[0609]

[0610] Compound 104D (0.285 g, 0.94 mmol) was subjected to the sameconditions as outlined in C2 (example 4) to yield the title compound(0.145 g, 94%). LC-MS: Column C, retention time=3.45 minutes, m/z 522.26(M+H)⁺.

EXAMPLE 1052-[2,3-Dihydro-3-(methylamino)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0611]

[0612] To 104 (0.14 g, 0.26 mmol) in 20 mL of methanol was added 10%Palladium on carbon (0.09 g) and the contents hydrogenated at 40 psi forsix hours. The reaction mixture was filtered and the filtrateconcentrated to yield the title compound (0.063 g, 61%). LC-MS: ColumnA, retention time=2.46 minutes, m/z 388.12 (M+H)+

EXAMPLE 106 2-[2,3-Dihydro-3-(1-pyrrolidinyl)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0613]

Example 106, Part A 1-(6-Bromo-2,3-dihydro-1H-inden-1-yl)pyrrolidine

[0614]

[0615] 6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the sameconditions as 104, part A by substituting methylamine with pyrrolidine(1.16 mL, 14 mmol) to yield the title compound (0.195 g, 52%). ¹H NMR(CDCl₃): 7.4 (s, 1H), 7.25 (d, 1H), 7.0 (d, 1H), 4.1 (t, 1H), 2.9 (m,1H), 2.6 (m, 1H), 2.55 (m, 4H), 2.1 (m, 2H), 1.7 (brs, 4H).

Example 106 Part B 1-(6-Ethynyl-2,3-dihydro-1H-inden-1-yl)pyrrolidine

[0616]

[0617] Compound 106A (0.195 g, 0.73 mmol) was subjected to the sameconditions as 104, part B and C to yield the title compound (0.130 g,84%). LC-MS: Column A, retention time=1.85 minutes, m/z 212.17 (M+H)⁺.

Example 106, Part C2-[2,3-Dihydro-3-(1-pyrrolidinyl)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0618]

[0619] Compound B (0.13 g, 0.63 mmol) was subjected to the sameconditions as outlined in C2 (example 4) to yield the title compound(0.007 g). LC-MS: Column C, retention time=2.36 minutes, m/z 428.24(M+H)⁺.

EXAMPLE 1072-[2,3-Dihydro-3-(4-morpholinyl)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0620]

Example 107, Part A 1-(6-Bromo-2,3-dihydro-1H-inden-1-yl)morpholine

[0621]

[0622] 6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the sameconditions as 104, part A by substituting methylamine with morpholine(4.0 mL) in toluene (5 mL) to yield the title compound (0.35 g, 89%). ¹HNMR (CDCl₃): 7.5 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 4.2 (t, 1H), 3.7(brs, 4H), 2.8 (m, 1H), 2.7 (m, 1H), 2.4 (m, 4H), 2.1 (m, 2H).

Example 107, Part B 4-(6-Ethynyl-2,3-dihydro-1H-inden-1-yl)morpholine

[0623]

[0624] Compound 107A (0.35 g, 1.24 mmol) was subjected to the sameconditions as 104, part B and C to yield the title compound (0.243 g,86%). LC-MS: Column A, retention time=1.73 minutes, m/z 228.14 (M+H)⁺.

Example 107, Part C2-[2,3-Dihydro-3-(4-morpholinyl)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0625]

[0626] Compound 104B (0.233 g, 1.04 mmol) was subjected to the sameconditions as outlined in C2 (example 4) to yield the title compound(0.045 g). LC-MS: Column C, retention time=2.34 minutes, m/z 444.25(M+H)⁺.

EXAMPLE 1082-[3-(1-Azetidinyl)-2,3-dihydro-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0627]

[0628] 6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the sameconditions as 104, part A by substituting methylamine with azetidine(0.9 mL 13.9 mmol) in toluene (5 mL) to yield the title compound (0.167g, 47%). ¹H NMR (CDCl₃): 7.3 (s, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 3.8 (m,1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.8 (m, 1H), 2.0 (m, 3H), 1.8 (m, 1H).

Example 108, Part B 1-(6-Ethynyl-2,3-dihydro-1H-inden-1-yl)azetidine

[0629]

[0630] Compound 108A (0.167 g, 0.66 mmol) was subjected to the sameconditions as 104, part B and C to yield the title compound (0.075 g,57%). LC-MS: Column A, retention time=1.67 minutes, m/z 198.11 (M+H)⁺.

Example 108, Part C,2-[3-(1-Azetidinyl)-2,3-dihydro-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0631]

[0632] Compound 108B (0.0.075 g, 0.391 mmol) was subjected to the sameconditions as outlined in C2 (example 4) to yield the title compound(0.015 g). LC-MS: Column C, retention time 2.32 minutes, m/z 414.26(M+H)⁺.

EXAMPLE 1097-Methoxy-2-[(3-methylphenyl)methyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0633]

Example 109, Part A 3-Methyl-b-oxobenzenebutanoic Acid Ethyl Ester

[0634]

[0635] m-tolylacetic acid (2.0 g, 13.33 mmol) was subjected to the sameconditions as outlined in method A3 (example 3) to yield the titlecompound (2.7 g, 92%). ¹H NMR (CDCl₃): □ 7.25 (m, 1H), 7.1 (d, 1H), 7.0(m, 2H), 4.2 (q, 2H), 3.8 (s, 2H), 3.4 (s, 2H), 2.4 (s, 3H), 1.2 (t,3H).

Example 109, Part B3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-4-(3-methylphenyl)-2-propenoicAcid Ethyl Ester

[0636]

[0637] Compound 109A (1.0 g, 4.54 mmol) was subjected to the sameconditions as outlined in method A3 (example 3) to yield the titlecompound (1.2 g, 67%).

Example 109, Part C7-Methoxy-2-[(3-methylphenyl)methyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0638]

[0639] Compound 109B (0.075 g, 0.391 mmol) was subjected to the sameconditions as outlined in A3 (example 4) to yield the title compound(0.6 g, 68%). LC-MS: Column A, retention time=3.21 minutes, m/z 347.05(M+H)⁺.

EXAMPLE 1102-(2,3-Dihydro-3-methoxy-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0640]

Example 110, Part A 6-Bromo-2,3-dihydro-1-methoxy-1H-indene

[0641]

[0642] To a solution of 6-bromoindanol (0.51 g, 2.4 mmol) in anhydroustetrahydrofuran (10 mL), was added sodium hydride (0.097 g, 3.84 mmol)over a period of five minutes at room temperature. The reaction mixturewas stirred at room temperature for fifteen minutes and iodomethane(0.22 mL, 3.6 mmol) was added. After thirty minutes at room temperature,the reaction mixture was partitioned between ethyl acetate (20 mL) andwater (20 mL). The ethyl acetate layer was washed with brine (20 mL),dried over sodium sulfate and concentrated to yield the title compound(0.485 g, 89%). ¹H NMR (CDCl₃): □ 7.5 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H),4.7 (m, 1H), 3.3 (s, 3H), 3.0 (m, 1H), 2.7 (m, 1H), 2.3 (m, 1H), 2.0 (m,1H).

Example 110, Part B 6-Ethynyl-2,3-dihydro-1-methoxy-1H-indene

[0643]

[0644] Compound 110A (0.485 g, 2.14 mmol) was subjected to the sameconditions as 104, part B and C to yield the title compound (0.35 g,95%). ¹H NMR (CDCl₃): □ 7.5 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 4.7 (m,1H), 3.3 (s, 3H), 3.0 (m, 1H), 2.9 (s, 1H), 2.7 (m, 1H), 2.3 (m, 1H),2.0 (m, 1H).

Example 110, Part C2-(2,3-Dihydro-3-methoxy-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0645]

[0646] Compound 110B (0.163 g, 0.94 mmol) was subjected to the sameconditions as outlined in C2 (example 4) to yield the title compound(0.05 g, 27%). LC-MS: Column A, retention time=3.17 minutes, m/z 389.11(M+H)⁺.

EXAMPLE 1112-(2,3-Dihydro-1-methyl-1H-isoindol-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0647]

Example 111, Part A 6-Ethynyl-2,3-dihydro-2-methyl-1H-isoindole

[0648]

[0649] 5-bromo-2-(N-methyl)isoindoline (prepared in a similar manner to5-bromoisoindoline, as reported in EP0343560) (0.1.1 g, 5.18 mmol) wassubjected to the same conditions as 104, part B and C to yield the titlecompound (0.298 g, 22%). LC-MS: Column A, retention time 1.05 minutes,m/z 158.04 (M+H)⁺.

Example 111, Part B2-(2,3-Dihydro-1-methyl-1H-isoindol-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0650]

[0651] Compound □□□□ (0.298 g ) was subjected to the same conditions asoutlined in C2 (example 4) to yield the title compound (0.05 g ). LC-MS:Column A, retention time=2.18 minutes, m/z 374.16 (M+H)⁺.

EXAMPLE 1127-Methoxy-2-[3-[(4-methoxyphenyl)methoxy]phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0652]

Example 112, Part A 3-[(4-Methoxyphenyl)methoxy]benzoic Acid MethylEster

[0653]

[0654] To a solution of methyl-3-hydroxybenzoate (5.0 g, 32.8 mmol) inacetone (30 mL) was added potassium carbonate (6.82 g, 49.2 mmol) andp-methoxybenzyl chloride (4.5 mL, 32.8 mmol). The contents are heatedunder reflux for forty eight hours, concentrated under pressure andpartitioned between ethyl acetate (100 mL) and water (100 mL). The ethylacetate layer was dried over sodium sulfate and concentrated to yieldthe title compound (8.87 g, 99%). ¹H NMR (CDCl₃): □ 7.8 (m, 2H), 7.4 (m,3H), 7.15 (m, 1H), 6.9 (d, 2H), 5.1 (s, 2H), 3.9 (s, 3H), 3.8 (s, 3H).

Example 112, Part B 3-[(4-Methoxyphenyl)methoxy]benzoic Acid

[0655]

[0656] To compound 112A (8.87 g, 32.61 mmol) in amixture of dioxane andwater (15:10 mL) was added lithium hydroxide (2.73 g, 65.22 mmol) andthe contents heated under reflux for two hours. The reaction mixture wasconcentrated and partitioned between ethyl acetate (2×300 mL) and water(600 mL). The aqueous layer was made acidic using 1N hydrochloric acid(aqueous) and extracted into ethyl acetate (2×300 mL). The ethyl acetatelayer was dried over sodium sulfate and concentrated to yield the titlecompound (8.2 g, 97%). ¹H NMR (DMSO-d6): □ 11. 0 (s, 1H), 7.6 (m, 2H),7.4 (m, 3H), 7.2 (m, 1H), 6.9 (d, 2H), 5.1 (s, 2H), 3.9 (s, 3H), 3.8 (s,3H).

Example 112, Part C 3-[(4-Methoxyphenyl)methoxy]-b-oxobenzenepropanoicAcid Ethyl Ester

[0657]

[0658] Compound 112B (8.1 g, 31.39 mmol) was subjected to the sameconditions as outlined in method A3 (example 3) to yield the titlecompound (9.8 g, 95%). ¹H NMR (CDCl₃): □ 7.6 (brs, 1H), 7.5 (d, 1H), 7.4(m, 3H), 7.2 (m,1H), 6.9 (d, 2H), 5.0 (s, 2H), 4.2 (q, 2H), 3.9 (s, 2H),3.8 (s, 3H), 1.2 (t, 3H).

Example 112, Part D3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-[3-[(4-methoxyphenyl)methoxy]phenyl]-2-propenoicAcid Ethyl Ester

[0659]

[0660] Compound 112C (5.0 g, 15.24 mmol) was subjected to the sameconditions as outlined in method A3 (example 3) to yield the titlecompound (5.5 g, 72%).

Example 112, Part E7-Methoxy-2-[3-[(4-methoxyphenyl)methoxy]phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0661]

[0662] Compound 112D (5.3 g, 10.6 mmol) was subjected to the sameconditions as outlined in A3 (example 4) to yield the title compound(2.8 g, 58%). LC-MS: Column A, retention time=3.54 minutes, m/z 455.10(M+H)⁺.

EXAMPLE 1132-(3-Hydroxyphenyl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0663]

[0664] To compound 112 (0.2 g, 0.44 mmol) was added trifluoroacetic acid(2 mL) and the contents stirred at room temperature for thirty minutes.The reaction mixture was concentrated and azeotroped twice with toluene.To the residue was added a mixture of methanol and ether (7:3 mL) andthe solid that separates out is filtered and dried to yield the titlecompound (0.14 g, 95%). LC-MS: Column A, retention time 2.8 minutes, m/z335.10 (M+H)⁺.

EXAMPLE 1142-[3-[2-(Dimethylamino)ethoxy]phenyl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0665]

Example 114, Part A7-Methoxy-2-[3-[(4-methoxyphenyl)methoxy]phenyl]-6-(5-oxazolyl)-4-(phenylmethoxy)quinoline

[0666]

[0667] To a solution of compound 112 (0.4 g, 0.88 mmol) in anhydrousdimethylformamide (10 mL) was added sodium hydride (0.027 g, 1.056 mmol)over a two minute period. The reaction mixture was heated for tenminutes at 80° C. followed by the addition of benzyl bromide (0.13 mL,1.056 mmol) at that temperature. The reaction mixture was heated for afurther ten minutes and concentrated under reduced pressure. To theresidue was added water (20 mL) and the solid that separates out isfiltered and dried to yield the title compound (0.475 g, 99%). LC-MS:Column A, retention time 3.69 minutes, m/z 545.12 (M+H)⁺.

Example 114, Part B3-[7-Methoxy-6-(5-oxazolyl)-4-(phenylmethoxy)-2-quinolinyl]phenol

[0668]

[0669] To compound 114A obtained above (0.475 g, 0.87 mmol) was addedtrifluoroacetic acid (6 mL) and the contents stirred at room temperaturefor forty minutes. The reaction mixture was concentrated and made basicby the slow addition of saturated aqueous sodium bicarbonate. The solidthat separates out was extracted into ethyl acetate (110 mL), dried oversodium sulfate and concentrated to yield the title compound (0.36 g,97%). LC-MS: Column A, retention time=3.24 minutes, m/z 425.08 (M+H)⁺.

Example 114, Part C2-[3-[7-Methoxy-6-(5-oxazolyl)-4-(phenylmethoxy)-2-quinolinyl]phenoxy]-N,N-dimethylethanamine

[0670]

[0671] To a solution of compound 114B (0.275 g, 0.65 mmol) in anhydrousdimethyformamide (10 mL) was added potassium carbonate (0.134 g, 0.975mmol) and the contents heated to 80° C. for two minutes.1-chloro-2-dimethylaminoethane (0.78 mL, 0.78 mmol of a 1.0M solution inchlorobenzene) was added and the contents heated at 80° C. for twohours. Additional potassium carbonate (2×0.134 g) and1-chloro-2-dimethylaminoethane (2×0.78 mL, 0.78 mmol of a 1.0M solutionin chlorobenzene) was added in one hour intervals at 80° C. The reactionmixture was concentrated and partitoned between dichloromethane (20 mL)and water (20 mL). The dichloromethane layer was dried over sodiumsulfate, concentrated and column purified using silica gel flash columnchromatography (dichloromethane/methanol as eluent) to yield the titlecompound (0.155 g, 48%). LC-MS: Column C, retention time=2.74 minutes,m/z 496.22 (M+H)⁺.

Example 114, Part D2-[3-[2-(Dimethylamino)ethoxy]phenyl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0672]

[0673] To a solution of compound 114C in methanol (0.155 g, 0.31 mmol)was added 10% palladium on carbon (0.07 g) and the contents hydrogenatedat 20 psi for two hours. The reaction mixture was filtered and thefilter pad washed with methanol (3×10 mL). The filtrate was concentratedunder reduced pressure to yield the title compound (0.119 g, 94%).LC-MS: Column A, retention time=2.23 minutes, m/z 406.37 (M+H)⁺.

EXAMPLE 1157-Methoxy-2-[3-[2-(4-morpholinyl)ethoxy]phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0674]

[0675] The title compound was made in a manner similar to 114 employing2-chloroethylmorpholine in place of 1-chloro-2dimethylaminoethane instep C. LC-MS: Column A, retention time=2.29 minutes, m/z 448 (M+H)⁺.

EXAMPLE 116 6-Methoxy-7-(5-oxazolyl)-3-phenyl-2H-1,4-benzothiazine1,1-dioxide

[0676]

Example 116, Part A[[2-Amino-4-methoxy-5-(5-oxazolyl)phenyl]thio]carbonitrile

[0677]

[0678] To a solution of 1D (2.0 g, 10.52 mmol) in methanol (20 mL) wasadded ammonium thiocyanate (1.6 g, 21.04 mmol). The contents were cooledto -5° C. and bromine (0.34 mL, 6.62 mmol) was added dropwise. Thereaction mixture was stirred at −5° C. for 10 minutes and at roomtemperature for twenty minutes. The solid that separates out was washedwith water (2×20 mL), ethanol (2×10 mL) and dried to yield the titlecompound (1.4 g, 54%). ¹H NMR (DMSO-d6): 8.32 (s, 1H), 7.67 (s, 1H),7.28 (s, 1H), 6.56 (s, 1H), 6.3 (brs, 2H), 3.88 (s, 3H).

Example 116, Part BN-[5-Methoxy-4-(5-oxazolyl)-2-(thiocyanato)phenyl]acetamide

[0679]

[0680] To a solution of 116A (0.4 g, 1.62 mmol) in dichloromethane (10mL) was added triethylamine (0.22 mL, 1.62 mmol) and the contents cooledto 0° C. Acetyl chloride (0.11 mL, 1.62 mmol) was added and the contentsstirred at room temperature for one hour. The reaction mixture wasfiltered and the solid washed with dichloromethane (2×10 mL) and driedto yield the title compound (0.436 g, 93%). LC-MS: Column A, retentiontime=2.06 minutes, m/z 290.3 (M+H)⁺.

Example 116, Part CN-[5-Methoxy-4-(5-oxazolyl)-2-[(2-oxo-2-phenylethyl)thio]phenyl]acetamide

[0681]

[0682] To a solution of 116B (0.396 g, 1.37 mmol) in a mixture ofethanol and dimethylformamide (10:3 mL), at 0° C. was added sodiumborohydride (0.104 g, 2.74 mmol) in one lot. After five minutes, acetone(5 mL) was added and the reaction mixture stirred at room temperaturefor one minute. 2-bromoacetophenone (0.272 g, 1.37 mmol) was added inone lot and the contents stirred at room temperature for forty fiveminutes. The reaction mixture was concentrated under reduced pressure.To the residue that is obtained was added ethyl acetate (10 mL). Thesolid that is thrown out (0.035 g) was filtered and dried to yield thetitle compound. The filtrate was concentrated and subjected to silicagel flash column chromatography (dichloromethane/ethyl acetate aseluent) to yield another batch of the title compound (combined yield:0.120 g, 23%). LC-MS: Column A, retention time =3.14 minutes, m/z 383.08(M+H)⁺.

Example 116, Part DN-[5-Methoxy-4-(5-oxazolyl)-2-[(2-oxo-2-phenylethyl)sulfonyl]phenyl]acetamide

[0683]

[0684] To a solution of 116C (0.12 g, 0.31 mmol) in acetic acid (5 mL)was added a few crystals of sodium tungstate followed by hydrogenperoxide (30% aqueous solution, 0.1 mL, 0.93 mmol) at room temperature.The raction mixture was stirred at room temperature for eighteen hoursand the solid that is thrown out was filtered, washed with water anddried to yield the title compound (0.105 g, 81%). LC-MS: Column A,retention time=2.96 minutes, m/z 415.03 (M+H)⁺.

Example 116, Part E6-Methoxy-7-(5-oxazolyl)-3-phenyl-2H-1,4-benzothiazine 1, 1-dioxide

[0685]

[0686] A solution of 116D (0.105 g, 0.25 mmol) in 4N aqueoushydrochloric acid (3 mL) was heated at 110° C. for one hour. Thereaction mixture was cooled to room temperature and the solid thatseparates out was filtered, washed with water (3×10 mL) and dried toyield the title compound (0.055 g, 61%). LC-MS: Column A, retentiontime=2.94 minutes, m/z 355.07 (M+H)⁺.

EXAMPLE 1176-Methoxy-3-(4-methoxyphenyl)-7-(5-oxazolyl)-2H-1,4-benzothiazine1,1-dioxide

[0687]

[0688] The title compound was made in a manner similar to 116 employing2-bromo-4′methoxyacetophenone in place of 2-bromoacetophenone in step116C. LC-MS: Column A, retention time=3.09 minutes, m/z 384.97 (M+H)⁺.

EXAMPLE 1183-Hydroxy-7-methoxy-6-(5-oxazolyl)-2-phenyl-4(1H)-quinolinone

[0689]

Example 118, Part A 2-Amino-4-methoxy-5-(5-oxazolyl)benzoic Acid MethylEster

[0690]

[0691] A steel bomb was charged with iodo aniline (1.18 g, 3.73 mmol)DMF (15 ml) bis(triphenylphosphine)palladium(II) dichloride (135 mg,0.19 mmol), triethylamine (1.56 ml, 11.4 mmol), and methanol (20 ml).The reaction mixture was heated at 120° C. under a carbon monoxideatmosphere for eighteen hours, cooled to room temperature, concentratedunder reduced pressure and purified by silica gel flash columnchromatography employing ethyl acetate/hexane (2:3) to yield the titlecompound (706 mg, 76%). ¹H NMR (CDCl₃) δ 3.81 (s, 3H), 3.86 (s, 3H) 6.10(s, 1H), 7.37 (s, 1H), 7.80 (s, 1H), 8.20 (s, 1H).

Example 118, Part B 2-Amino-4-methoxy-5-(5-oxazolyl)benzoic Acid

[0692]

[0693] To the methyl ester (706 mg, 2.85 mmol) was added lithiumhydroxide (251 mg, 5.97 mmol), water (5 ml) THF (20 ml) and MeOH (20ml). The reaction mixture was heated under reflux for eighteen hours andconcentrated under reduced pressure. The pH of the reaction was adjustedto 4-5 employing 1 N HCl. The solid that separates out was filteredrinsed with water and dried to yield the title compound (630 mg, 94%).¹H NMR (DMSO) δ 3.89 (s, 3H), 6.45 (s, 1H), 7.0 (br, 2H), 7.26 (s, 1H),8.06 (s, 1H), 8.29 (s, 1H), 12.0 (broad, 1H).

118B Example 118, Part C 2-Amino-4-methoxy-5-(5-oxazolyl)benzoic Acid2-oxo-2-phenylethyl Ester

[0694]

[0695] To a solution of acid 118B (0.279 g, 1.19 mmol) in acetone (10ml) was added potassium carbonate (0.215 g, 1.19 mmol) and the contentsstirred at room temperature for 30 min. Then 2-bromoacetophenone (0.236g, 1.19 mmol) was added and the reaction mixture was heated under refluxfor eighteen hours. The reaction mixture was concentrated under reducedpressure and partitioned between dichloromethane (20 mL) and water (20mL). The dichloromethane layer was dried over sodium sulfate andconcentrated under reduced pressure to yield the title compound (0.410g, 97%). LC-MS: Column A, retention time=3.25 minutes, m/z 353.09(M+H)⁺.

Example 118, Part C3-Hydroxy-7-methoxy-6-(5-oxazolyl)-2-phenyl-4(1H)-quinolinone

[0696]

[0697] To phosphorous pentoxide (0.073 g, 0.51 mmol) in1,2-dichlorobenzene (2 mL) was added hexamethyldisiloxane (0.43 mL, 2.04mmol) and the contents heated at 150° C. for thirty minutes. To theclear solution was added 118B (0.06 g, 0.17 mmol) and the contentsheated at 150° C. for 2.5 hours. The reaction mixture was cooled to roomtemperature and filtered. The solid is washed with ethyl acetate (5×10mL), water (10 mL), saturated aqueous sodium bicarbonate (10 mL), water(10 mL) and dried to yield the title compound (0.035 g, 61%). LC-MS:Column A, retention time 2.88 minutes, m/z 335.38 (M+H)⁺.

EXAMPLE 1193-Hydroxy-7-methoxy-2-(2-methylphenyl)-6-(5-oxazolyl)-4(1H)-quinolinone

[0698]

[0699] The title compound was made in a manner similar to 118 employing2-bromo-2′ methylacetophenone in place of 2-bromoacetophenone in step118A. LC-MS: Column C, retention time=2.82 minutes, m/z 349.12 (M+H)⁺.

EXAMPLE 1203-Hydroxy-7-methoxy-2-(3-methylphenyl)-6-(5-oxazolyl)-4(1H)-quinolinone

[0700]

[0701] The title compound was made in a manner similar to 118 employing2-bromo-3′ methylacetophenone in place of 2-bromoacetophenone in step118A. LC-MS: Column A, retention time=3.04 minutes, m/z 349.18 (M+H)⁺.

EXAMPLE 1213-Hydroxy-7-methoxy-2-(4-methylphenyl)-6-(5-oxazolyl)-4(1H)-quinolinone

[0702]

[0703] The title compound was made in a manner similar to 118 employing2-bromo-4′ methylacetophenone in place of 2-bromoacetophenone in step118A. LC-MS: Column A, retention time=3.13 minutes, m/z 349.37 (M+H)⁺.

EXAMPLE 1222-(3,4-Dimethylphenyl)-3-hydroxy-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0704]

[0705] The title compound was made in a manner similar to 118 employing2-bromo-3′,4′ methylacetophenone in place of 2-bromoacetophenone in step118A. LC-MS: Column A, retention time=3.26 minutes, m/z 363.18 (M+H)⁺.

EXAMPLE 123 3-Hydroxy-7-methoxy-2-(4-methoxyphenyl)-6-(5-oxazolyl)-4(1H)-quinolinone

[0706]

[0707] The title compound was made in a manner similar to 118 employing2-bromo-4′ methoxyacetophenone in place of 2-bromoacetophenone in step118A. LC-MS: Column A, retention time=2.89 minutes, m/z 365.13 (M+H)⁺.

EXAMPLE 1242-(4-Chloro-3-methylphenyl)-3-hydroxy-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0708]

Example 124, Part A 2-Amino-4-methoxy-5-(5-oxazolyl)benzoic acid2-(4-chloro-3-methylphenyl)-2-oxoethyl Ester

[0709]

[0710] The title compound was made in a manner similar to 118 employing2-bromo-4′ chloro-3′ methylacetophenone in place of 2-bromoacetophenonein step 118A.

Example 124, Part B2-(4-Chloro-3-methylphenyl)-3-hydroxy-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0711]

[0712] To a solution of 124A (0.06 g, 0.15 mmol) in acetic acid (1.5 mL)was added ammonium acetate (0.044 g, 2.25 mmol) and the contents heatedat 120° C. for eighteen hours. The reaction mixture was concentrated andpartitioned between dichloromethane/methanol (8:2, 20 mL) and water (20mL). The dichloromethane/methanol layer was dried over sodium sulfateand concentrated. To the residue was added methanol and the solid thatseparates out was filtered. The filtrate was concentrated under reducedpressure and purified by preparative HPLC to yield the title compound(0.005 g) as the trifluoroacetic acid salt. LC-MS: Column A, retentiontime=3.44 minutes, m/z 383 (M+H)⁺.

EXAMPLE 125 2-(2,3-Dihydro-3-methoxy-1H-inden-5-yl)-3-hydroxy-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0713]

Example 125, Part A 2-Bromo-1-(2,3-dihydro-3-methoxy-1H-inden-5-yl)ethanone

[0714]

[0715] To a solution of 110A (0.525 g, 2.31 mmol) in anhydrous dioxane(10 mL) was sequentially added tributyl(1-ethoxyvinyl)tin (0.82 mL, 2.42mmol) and bis(triphenylphosphine)palladium(II)dichloride (0.081 g, 0.11mmol). The reaction mixture was heated at 100° C. for eighteen hours,cooled to room temperature and filtered. To the filtrate was added water(10 mL) followed by N-bromosuccinamide (0.452 g, 2.54 mmol) and thecontents stirred at room temperature for one hour. The reaction mixturewas partitioned between ethyl acetate (2×20 mL) and water (10 mL). Theethyl acetate layer was washed with brine, dried over sodium sulfate,concentrated and purified by silica gel flash chromatography(hexane/ethyl acetate, 9:1 as eluent) to yield the title compound (0.495g, 79%). ¹H NMR (CDCl₃): □ 7.93 (s, 1H), 7.85 (d, 1H), 7.3 (d, 1H), 4.8(m, 1H), 4.4 (m, 2H), 3.4 (s, 1H), 3.1 (m, 1H), 2.85 (m, 1H), 2.4 (m,1H), 2.1 (m, 1H).

Example 125, Part B2-(2,3-Dihydro-3-methoxy-1H-inden-5-yl)-3-hydroxy-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0716]

[0717] The title compound was made in a manner similar to 118 employing125A in place of 2-bromoacetophenone in step A. LC-MS: Column A,retention time 3.01 minutes, m/z 405.17 (M+H)⁺.

EXAMPLE 1263-Hydroxy-7-methoxy-2-[2-(methylsulfonyl)phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0718]

[0719] To 118A (125 mg. 0.35 mmol) was added Eaton's reagent (4.5 ml)and the contents heated at 100° C. for 2.5 hr. The reaction mixture waspoured into crushed ice and extracted with dichloromethane. Thedichloromethane layer is successively washed with sat. aqueous sodiumbicarbonate, brine, dried over sodium sulfate, concentrated and purifiedby silica gel flash chromatography (100% Ethyl acetate as eluent) togive the title compound (10 mg). LC-MS: Column A, retention time=3.04minutes, m/z 413.04 (M+H)⁺.

EXAMPLE 1272-[1-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0720]

Example 127, Part A 5-Bromo-2,3-dihydro-N,N-dimethyl-1H-inden-1-amine

[0721]

[0722] To a solution of 5-bromo-1-chloro-indane (542 mg, 2.35 mmol) intoluene (9 ml) was added dimethylamine (3 ml) and resulting mixture washeated at 90° C. for 1.5 hr. The reaction mixture is concentrated underreduced pressure to yield the title compound (300 mg, 53%). ¹H NMR(CDCl₃): 2.06 (m, 2H), 2.24 (s, 6H), 2.81-2.93 (m, 2H) 4.27 (t, 1H),7.22 (d, 1H), 7.33 (d 1H), 7.36 (s, 1H).

Example 127, Part B2-[1-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0723]

[0724] Compound 127A was subjected to the conditions outlined in C2 toyield the title compound. LC-MS: Column A, retention time=2.41 minutes,m/z 402.15 (M+H)⁺.

EXAMPLE 1282-(2,3-Dihydro-3-methoxy-2,2-dimethyl-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0725]

[0726] This compound was prepared using conditions outlined in C2 andusing 5-Bromo-2, 2-dimethyl-1-hydroxy-indane. LC-MS: Column A, retentiontime=3.50 minutes, m/z 417.13 (M+H)⁺.

EXAMPLE 1292-(2,3-Dihydro-3-methoxy-1,1-dimethyl-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0727]

Example 129, Part A 5-Bromo-2,3-dihydro-3-methoxy-1,1-dimethyl-1H-indene

[0728]

[0729] To a solution of 5-Bromo-3,3-dimethyl-1-hydroxy-indane (200 mg,0.83 mmol) in THF was added sodium hydride (32 mg, 1.33 mmol) andresulting mixture was stirred for 15 min. Iodomethane was added dropwiseand stirring continued for 1 hr. The reaction mixture was concentratedunder reduced pressure, extracted into ethyl acetate, washed with H₂O,dried over Na₂SO₄, concentrated and purified using silica gel flashchromatography (EtOAc/Hex, 1:5 as eluent) to yield the title compound(105 mg). ¹H NMR(CDCl₃): □ 1.14 (s, 3H), 1.28 (s, 3H), 1.85 (s, 1H),2.18 (s, 1H), 3.34 (s, 3H), 4.70 (t, 1H), 6.98 (s, 1H), 7.222 (d, 1H),7.41 (s, 1H).

Example 129, Part B2-(2,3-Dihydro-3-methoxy-1,1-dimethyl-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0730]

[0731] Compound 129A was subjected to the conditions outlined in C2 toyield the title compound. LC-MS: Column A, retention time=3.41 minutes,m/z 417.13(M+H)⁺.

EXAMPLE 130trans-2-[3-(Dimethylamino)-2,3-dihydro-2-methoxy-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0732]

Example 130, Part Atrans-6-Bromo-2,3-dihydro-2-hydroxy-N,N-dimethyl-1H-inden-1-amine

[0733]

[0734] A mixture of 5-bromoindene (608 mg, 3.12 mmol) and m-CPBA (804mg, 3.27 mmol) in CH₂Cl₂ was stirred at room temperature for eighteenhours. The solid that separated out was filtered. The filtrate wasconcentrated under reduced pressure and subjected to silica gel flashchromatography (EtOAc/Hex 1:8 as eluent) to give the epoxide (350 mg,53%) which was used as such for the subsequent step.

[0735] To the epoxide obtained above (350 mg, 1.66 mmol), dimethylamine(5.6 M in ethanol, 3 ml) was added and the contents heated in a sealedtube at 100° C. for eighteen hours. The reaction mixture wasconcentrated under reduced pressure and the residue partitioned betweenethyl acetate (30 mL) and 1N HCl (15 ml). The HCl layer was basifiedwith 1 N NaOH and extracted into EtOAc, washed with brine, dried overNa₂SO₄ and concentrated to yield the title compound (420 mg, 95%). ¹HNMR (CDCl₃): □ 2.37 (s, 6H), 2.70 (q, 1H), 3.15 (q, 1H), 4.06 (d, 1H),4.60 (q, 1H), 7.02 (d, 1H), 7.29 (d, 1H), 7.42 (s, 1H)

Example 130, Part Btrans-6-Bromo-2,3-dihydro-2-methoxy-N,N-dimethyl-1H-inden-1-amine

[0736]

[0737] Compound 130A was methylated analogous to 129 (part A) to yieldthe title compound.

Example 130, Part Ctrans-2-[3-(Dimethylamino)-2,3-dihydro-2-methoxy-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0738]

[0739] Compound 130B was subjected to the conditions outlined in C2 toyield the title compound. LC-MS: Column A, retention time=2.69 minutes,m/z 432.09(M+H)⁺.

EXAMPLE 131trans-2-[3-(Dimethylamino)-2,3-dihydro-2-hydroxy-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0740]

[0741] Compound 130 was subjected to the conditions outlined in C2 toyield the title compound. LC-MS: Column A, retention time=2.40 minutes,m/z 418.07(M+H)⁺.

EXAMPLE 132trans-6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-1-(dimethylamino)-2,3-dihydro-1H-inden-2-olMethylcarbamate

[0742]

[0743] A mixture of 131 (50 mg, 0.12 mmol), methyl isocyanate (15 mg,0.14 mmol) in pyridine (1 ml) was heated at 65° C. for 2 hr. Thereaction mixture was concentrated under reduced pressure and to theresidue was added ethyl acetate. The solid that separates out isfiltered and dried to yield the title compound (15 mg). LC-MS: Column A,retention time=2.59 minutes, m/z 475.16(M+H)⁺.

EXAMPLE 133 Ethylcarbamic acidtrans-6-[1,4-dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-1-(dimethylamino)-2,3-dihydro-1H-inden-2-ylester

[0744]

[0745] This compound was prepared analogous to 132 using ethylisocyanate. LC-MS: Column A, retention time=2.76 minutes, m/z 489.16(M+H)⁺.

EXAMPLE 134 (1-Methylethyl)carbamic acidtrans-6-[1,4-dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-1-(dimethylamino)-2,3-dihydro-1H-inden-2-ylester

[0746]

[0747] This compound was prepared analogous to 132 using isopropylisocyanate. LC-MS: Column A, retention time=2.46 minutes, m/z503.17(M+H)⁺.

EXAMPLE 135 (2-Chloroethyl)carbamic acidtrans-6-[1,4-dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-1-(dimethylamino)-2,3-dihydro-1H-inden-2-ylEster

[0748]

[0749] This compound was prepared analogous to 132 using 2-chloroethylisocyanate. LC-MS: Column A, retention time =2.79 minutes, m/z523.07(M+H)⁺.

EXAMPLE 136 Imidodicarbonic Acidtrans-6-[1,4-dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-1-(dimethylamino)-2,3-dihydro-1H-inden-2-ylMethyl Ester

[0750]

[0751] This compound was prepared analogous to 132 using methylisocyanatoformate. LC-MS: Column A, retention time=2.61 minutes, m/z519.12 (M+H)⁺.

EXAMPLE 1377-Methoxy-2-[4-methyl-3-(phenylmethoxy)phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0752]

Example 137, Part A 4-Methyl-b-oxo-3-(phenylmethoxy)benzenepropanoicAcid Ethyl Ester

[0753]

[0754] Compound 137A was prepared from 3-benzyl-4-methylbenzoic acid inan analogous way to Method A3 (Example 3). HPLC retention time: 1.770min.; Column conditions B. Example 2, Part B,7-Methoxy-2-[4-methyl-3-(phenylmethoxy)phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone137 was prepared from 137A in a similar method to Method A2 (Example 2)with pyridinium p-toluenesulfonate used for the H+ source and diphenylether replacing xylene in the cyclization step. HPLC retention time:1.814 min.; Column conditions B; 439⁺ (M+H)⁺.

EXAMPLE 1382-(3-Hydroxy-4-methylphenyl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0755]

Example 138, Part A7-Methoxy-4-(methoxymethoxy)-2-[4-methyl-3-(phenylmethoxy)phenyl]-6-(5-oxazolyl)quinoline

[0756]

[0757] Compound 138A was prepared from 137 in an analogous method to thefirst step in Method B1 (Example 3) with the reaction being run at 70°C. HPLC retention time: 1.711 min.; Column conditions B.

Example 138, Part B2-(3-Hydroxy-4-methylphenyl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0758] 138 was prepared from 138A through hydrogenation using palladiumon activated carbon (10%), H₂, and MeOH/THF (12.5:1 ratio) as solvent.HPLC retention time: 2.886 min.; Column conditions: YMC S5 ODS 4.6×50mm; Gradient time: 4 min.; Flow rate=4 ml/min.; Solvent A=10% MeOH, 90%H₂O, 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, 0.1% TFA; Start % B=0; Final% B 100; 349⁺ (M+H)⁺.

EXAMPLE 1397-Methoxy-2-[3-(2-methoxyethoxy)-4-methylphenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0759]

Example 139, Part A5-[7-Methoxy-4-(methoxymethoxy)-6-(5-oxazolyl)-2-quinolinyl]-2-methylphenol

[0760]

[0761] 139A was prepared from 138A through hydrogenation using palladiumon activated carbon (10%), H₂, and MeOH/THF (12.5:1 ratio) as solvent.HPLC retention time: 1.458 min.; Column conditions B.

Example 139, Part B7-Methoxy-2-[3-(2-methoxyethoxy)-4-methylphenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0762] 139 was prepared by coupling 138A with 2-chloroethyl methyl etherusing K₂CO₃ in DMF at 80° C. Aqueous work up done before compounds weredeprotected using TFA in CH₂Cl₂. Products then purified by Prep HPLC.HPLC retention time: 1.58 min.; column conditions B; (M+H)+407.

EXAMPLE 1407-Methoxy-2-[4-methyl-3-[(1-methyl-3-piperidinyl)methoxy]phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0763]

[0764] 140 was prepared by coupling 138A with the respective3-chloromethyl-1-methyl piperdine using K₂CO₃ in DMF at 80° C. Aqueouswork up done before compounds were deprotected using TFA in CH₂Cl₂.Products then purified by Prep HPLC. HPLC retention time: 1.41 min.;column conditions B; (M+H)+460.

EXAMPLES 141-149

[0765] Examples 141-149 were prepared using 138A, the respectivealcohols, diethyl azodicarboxylate, and triphenylphosphine in THF.Compounds were purified by normal phase silica gel column before beingdeprotected with TFA in CH₂Cl₂. Compounds then purified by either normalphase silica gel column or by Prep HPLC. TABLE 2

HPLC conditions retention time LC-MS Ex. No. Compound Name R¹ (min.)(M + H)⁺ 141 7-Methoxy-2-[4- methyl-3-[2-(4- morpholinyl)eth-oxy]phenyl]-6-(5- oxazolyl)-4(1H)- quinolinone

B/1.27 462⁺ 142 7-Methoxy-2-[4- methyl-3-[[2- (1H-imidazol-1-yl)ethoxy]phenyl]- 6-(5- oxazolyl)-4(1H)- quinolinone

F/1.35 443⁺ 143 2-[3-[2- (Dimethylamino)eth- oxy]-4- methylphenyl]-7-methoxy-6-(5- oxazolyl)-4(1H)- quinolinone

F/1.35 420⁺ 144 7-Methoxy-2-]4- methyl-3- [(tetrahydro-3-furanyl)methoxy]phenyl]-6-(5- oxazolyl)-4(1H)- quinolinone

B/1.57 433⁺ 145 7-Methoxy-2-[4- methyl-3-[(1- methyl-4-piperidinyl)oxy]phenyl]-6-(5- oxazolyl)-4(1H)- quinolinone

B/1.32 446⁺ 146 7-Methoxy-2-[4- methyl-3-[[(2S)- 1-methyl-2-pyrrolidinyl]meth- oxy]phenyl]-6- (5-oxazolyl)- 4(1H)- quinolinone

B/1.33 446⁺ 147 7-Methoxy-2-[4- methyl-3-[(1- methyl-3-pyrrolidinyl)oxy]phenyl]-6-(5- oxazolyl)-4(1H)- quinolinone

B/1.30 432⁺ 148 7-Methoxy-2-[4- methyl-3-[2-(2-pyridinyl)ethoxy]phenyl]-6-(5- oxazolyl)-4(1H)- quinolinone

C/2.64 454⁺ 149 7-Methoxy-2-[4- methyl-3- [(tetrahydro-2-furanyl)methoxy]phenyl]-6-(5- oxazolyl)-4(1H)- quinolinone

A/3.24 433⁺

EXAMPLE 1506-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-N,N,N-trimethyl-1H-inden-1-aminium

[0766]

[0767] 150 was prepared by methylating 10 using K₂CO₃ and methyl iodidein acetone refluxing at 48° C. Compound was purified by Prep HPLC. HPLCretention time: 1.20 min.; column condition B; (M+H)⁺ 417⁺.

EXAMPLE 1512-[3-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl]-3-hydroxy-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0768]

Example 151, Part A6-(Bromoacetyl)-2,3-dihydro-N,N-dimethyl-1H-inden-1-amine

[0769]

[0770] 151A was prepared from 10A by an analogous method described forthe preparation of 110A.

Example 151, Part B 2-Amino-4-methoxy-5-(5-oxazolyl)benzoic acid2-[2,3-dihydro-3-(dimethylamino)-1H-inden-5-yl]-2-oxoethyl Ester

[0771]

[0772] A mixture of 118B (58 mg, 0.246 mmol) and potassium carbonate (75mg, 0.542 mmol) in dry DMF (1.0 mL) was heated to 90° C. for 1 hr, thencooled to 0° C. A solution of Compound 1b (69 mg, 0.246 mmol) in 1.0 mLof dry DMF was added and the mixture was stirred at ambient temperaturefor 2.0 hr. The reaction mixture partitioned between ethyl acetate andice water, extracted with ethyl acetate (2X). The combined organicextracts were washed once with 10% LiCl aq. solution, dried overanhydrous Na₂SO₄. Concentration in vacuo followed by flashchromatography (CH₂Cl₂-MeOH: 95:5) on silica gel afforded 50 mg of 151Bas a colorless oil.

Example 151, Part C2-[3-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl]-3-hydroxy-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0773] A mixture of Compound 151B (27 mg, 0.062 mmol), p-TsOHmonohydrate (24 mg, 0.124 mmol) and propionic acid (92 mg, 1.24 mmol) in2 mL of dry toluene was heated to reflux for 4.0 hr. After the solventwas removed under reduced pressure, the residue was taken into CH₂Cl₂and washed with pH 7.0 buffer solution. The organic layer was dried overanhydrous Na₂SO₄. Concentration in vacuo followed by flashchromatography (CH₂Cl₂-MeOH-NH₄OH: 90:10:0 to 90:10:1) on silica gelafforded 23.8 mg of the target compound as a yellow solid. HPLCretention time: 2.289 min (Column conditions C). LC-MS: 418⁺ (M+H)⁺.

EXAMPLE 1521,4-Dihydro-3-hydroxy-7-methoxy-2-(4-methylphenyl)-4-oxo-6-quinolinecarbonitrile

[0774]

Example 152, Part A 2-Amino-5-cyano-4-methoxybenzoic Acid

[0775]

[0776] Compound 152A was prepared by an analogous method as that of 118Bstarting from 3-methoxy-4-cyanoaniline.

Example 152, Part B 2-Amino-5-cyano-4-methoxybenzoic acid2-(4-methylphenyl)-2-oxoethyl Ester

[0777]

[0778] 152B was prepared by an analogous method as that of 151B startingfrom Compound 152A.

Example 152, Part C1,4-Dihydro-3-hydroxy-7-methoxy-2-(4-methylphenyl)-4-oxo-6-quinolinecarbonitrile

[0779] 152 was prepared by an analogous method described for thepreparation of 151.HPLC retention time: 2.836 min (Column conditions C).LC-MS: 307⁺ (M+H)⁺.

EXAMPLE 1531,4-Dihydro-3-hydroxy-7-methoxy-2-(3-methylphenyl)-4-oxo-6-quinolinecarbonitrile

[0780]

[0781] 153 was prepared by an analogous method as that of Compound152.HPLC retention time: 2.806 min (Column conditions C). LC-MS: 307⁺(M+H)⁺.

EXAMPLE 154 7-Methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0782]

Example 154, Part A5-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0783]

[0784] To 1D (500 mg, 2.6 mmol) in MeOH (5 mL) at room temperature wasadded 5-(Methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (490 mg,2.6 mmol). The mixture was stirred at room temperature for 15 min thencooled in an ice bath and the solid filtered with cold MeOH rinse togive 880 mg (97%) of a yellow solid solid.

Example 154, Part B 7-Methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0785] 154A (820 mg, 2.38 mmol) in diphenylether (10 mL) was heated in a200° C. bath for 2.5 h. The reaction was then cooled to room temperatureand 10 mL hexane was added. The solid was filtered to give 545 mg (95%)of the title compound as an off white solid. HPLC Ret. Time: 2.756 min(Method A). Mass Spec: 243 (M+H⁺).

EXAMPLE 155 7-Methoxy-2-(methylthio)-6-(5-oxazolyl)-4(1H)-quinolinone

[0786]

[0787] To 1D(500 mg, 2.63 mmol) in diphenylether (5 mL) was added5-[Bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (653 mg,2.63 mmol) and the mixture heated to 120° C. for 2 h. The reaction wasthen heated to 200° C. for 15 min then cooled to room temperature.Hexane was added to the mixture and the solid was filtered to give 675mg (89%) of the title compound as a yellow solid. HPLC Ret. Time: 2.316min (Method A). Mass Spec: 289 (M+H⁺)

EXAMPLE 1562-(2,3-Dihydro-3-hydroxy-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0788]

Example 156, Part A6-Bromo-2,3-dihydro-1-[[tris(1-methylethyl)silyl]oxy]-1H-indene

[0789]

[0790] To 6-Bromo-2,3-dihydro-1H-inden-1-ol (300 mg, 1.41 mmol) inCH₂Cl₂ (4 mL) was added 2,6-lutidine (151 μL, 1.4 mmol) followed bytriisopropylsilyltriflate (378 μL, 1.41 mmol) at room temperature. Thereaction was stirred for 30 min then added to 1N HCl and extracted. Theorganic layer was washed with saturated sodium bicarbonate then brineand dried over MgSO₄. The solvent was removed in vacuo and the crudematerial purified by column chromatography.

Example 156, Part B2,2-Dimethyl-5-[(methylthio)[3-[[tris(1-methylethyl)silyl]oxy]-1H-inden-5-yl]methylene]-1,3-dioxane-4,6-dione

[0791]

[0792] To 156A (843 mg, 1.72 mmol) in THF (10 mL) with magnesium (83 mg,3.43 mmol) at 50° C. was added catalytic dibromoethane. The reaction wascooled to room temperature then transferred via canula to5-[Bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (380 mg,1.53 mmol) in THF (10 mL). The reaction was quenched with 1N HCl andextracted with Et₂O. The organic layer was washed with brine, dried overMgSO₄, filtered and the solvent removed in vacuo. The crude product wasused as is in the next step.

Example 156, Part C7-Methoxy-6-(5-oxazolyl)-2-[3-[[tris(1-methylethyl)silyl]oxy]-1H-inden-5-yl]-4(1H)-quinolinone

[0793]

[0794] To crude 156B (1.5 mmol) in diphenylether (10 mL) was added 1D(290 mg, 1.52 mmol) and the reaction was heated to 140° C. for 6 h thenheated to 200° C. for 15 min. The reaction was cooled to roomtemperature and hexane was added, then the solid filtered and rinsedwith hexane to give 539 mg 156C. Example 156, Part D,2-(2,3-Dihydro-3-hydroxy-1H-inden-5-yl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinoneTo 156C (100 mg, 0.19 mmol) in MeOH (30 mL) was added 1N HCl (7 mL) andthe reaction stirred at room temperature for 18 h. The solvent was thenremoved in vacuo and water was added. The solid precipitate was filteredwith water rinse followed by Et₂O rinse to give 67 mg (95%) of the titlecompound as a off white solid. HPLC retention time: 2.749 min (MethodA). Mass Spec: 375 (M+H⁺).

EXAMPLE 1572-(3,4-Dimethoxyphenyl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0795]

Example 157, Part A5-[(3,4-Dimethoxyphenyl)[[3-methoxy-4-(5-oxazolyl)phenyl]amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0796]

[0797] 157A was prepared from 4-bromoveratrole (100 mg, 0.46 mmol) and5-[Bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (76 mg,0.3 mmol) using the same procedure as 156B to give 80 mg (78%).

Example 157, Part B5-[[5-[(Dimethylamino)methyl]-3-thienyl](methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0798]

[0799] To 157A (60 mg, 0.17 mmol) in EtOH (2 mL) was added 1D (34 mg,0.17 mmol) and the reaction was heated to reflux for 12 h. The reactionwas cooled in ice and the solid filtered with cold EtOH rinse to give 48mg of 157B.

Example 157, Part C2-(3,4-Dimethoxyphenyl)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0800] 157B (40 mg, 0.083 mmol) in diphenylether (700 μL) was heated to200° C. for 1 h then cooled to room temperature. Hexane was added to themixture and the solid filtered with hexane rinse to give 28 mg (87%)ofthe title compound. HPLC retention time: 2.756 min (Method A). MassSpec: 379 (M+H⁺).

EXAMPLE 1582-[5-[(Dimethylamino)methyl]-3-thienyl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0801]

Example 158, Part A5-[[5-[(Dimethylamino)methyl]-3-thienyl](methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0802]

[0803] To 4-Bromo-N,N-dimethyl-2-thiophenemethanamine (130 mg, 0.59mmol) in THF (2 mL) cooled to −78° C. was added n-BuLi (230 μL, 0.59mmol) dropwise. The reaction was stirred at −78° C. for 15 min then thereaction was rapidly tranfered via canula to5-[Bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (125 mg,0.50 mmol) in THF (2 mL) stirring at room temperature. The reaction wasquenched with 1N HCl and extracted with CH₂Cl₂ and saturated sodiumbicarbonate. The crude reaction residue was purified by columnchromatography to give 74 mg of 158A.

Example 158, Part B2-[5-[(Dimethylamino)methyl]-3-thienyl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0804] To 158A (74 mg, 0.21 mmol) in diphenylether (2 mL) was added 1D(41 mg, 0.21 mmol) and the reaction was heated to 120° C. for 6 h. Thereaction was heated to 200° C. for 10 min then cooled to roomtemperature. Hexane was added to the reaction and the solid was filteredwith hexane rinse to give 54 mg (67%) of the title compound. HPLCretention time: 2.033 min (Method A). Mass Spec: 382 (M+H⁺).

EXAMPLE 1592-[3-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinoneEnantiomer A;

[0805]2-[3-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinoneenantiomer B

Example 159, Part A5-[[3-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl](methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0806]

[0807] 159A was prepared from 10B (1.1 g, 4.58 mmol) and5-[Bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (755 mg,3.04 mmol) using the same procedure as 156B to give 1.2 g (72%).

Example 159, Part B

[0808] 159 was prepared from 159A (1.2 g, 3.32 mmol) and 1D (630 mg,3.32 mmol) using the same procedure as 158 to give 1.0 g (75%). HPLCretention time: 2.22 min. (Method A). Mass Spec: 402 (M+H⁺).

[0809] The two enantiomers were separated on a chiral preparative ASHPLC column eluted with 15% EtOH/Hexane with 0.12% Et₃N. The analyticalchiral HPLC retention time for the first enantioner A is 11.5 min on achiral AS analytical column eluted with 14% EtOH/Hexane with 0.12% Et₃Nat 2 mL/min on a 35 min run time. The second enantiomer B has aretention time on the analytical chiral AS column of 16.1 min using thesame conditions.

[0810] Both enantiomers gave identical retention times with method A andidentical Mass Spectra as given above.

EXAMPLE 160 7-Methoxy-2-(methylamino)-6-(5-oxazolyl)-4(1H)-quinolinone

[0811]

Example 160, Part A5-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino](methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0812]

[0813] To 1D (316 mg, 1.66 mmol) in MeOH (3 mL) was added5-[Bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (412.5mg, 1.66 mmol) and stirred at room temperature for 5 h. The reaction wascooled in an ice bath and filtered to give 620 mg (96%)of the titlecompound, as a yellow solid.

Example 160, Part B5-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino](methylamino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0814]

[0815] To 160A (60 mg, 0.154 mmol) in THF (2 mL) was added dimethylamine(1 mL, M in H₂O) followed by HgCl₂ (41.8 mg, 0.154 mmol) at roomtemperature. The reaction was stirred for 2 h at room temperature thenfiltered. Water was added and the mixture extracted 3 times with CH₂Cl₂.The organic layer was washed with brine and dried over MgSO₄. After thesolvent was removed the residue was purified by column chromatography togive 51.6 mg 160B.

Example 160, Part C7-Methoxy-2-(methylamino)-6-(5-oxazolyl)-4(1H)-quinolinone

[0816] 160B (51.6 mg, 0.14 mmol) in diphenylether (2 mL) was heated to250° C. for 2 h. The reaction was cooled to room temperature and hexanewas added. The solid was filtered and washed with hexane to give 29 mg(77%) of the title compound. HPLC retention time: 2.289 min (Method A).MassSpec: 272 (M+H⁺).

EXAMPLE 161 2-(Dimethylamino)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0817]

Example 161, Part A5-[(Dimethylamino)[[3-methoxy-4-(5-oxazolyl)phenyl]amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0818]

[0819] 161A was prepared from 160A (60 mg, 0.154 mmol) and dimethylamine(2 mL, M in EtOH) using the same procedure as 160B to give 35 mg.

Example 161, Part B 2-(Dimethylamino)-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0820] 161 was prepared from 161A (35 mg, 0.09 mmol) and diphenylether(1 mL) using the same procedure as 160 to give 16 mg (62%)of the titlecompound. HPLC retention time: 2.276 min (Method A). Mass Spec 286(M+H⁺).

EXAMPLE 162[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]methylcarbamicAcid 1,1-dimethylethyl Ester

[0821]

Example 162, Part A (6-Bromo-2,3-dihydro-1H-inden-1-yl)methylcarbamicacid 1,1-dimethylethyl Ester

[0822]

[0823] To 104A (650 mg, 2.86 mmol) in MeOH (2 mL) was addeddi-tertbutyldicarbonate (722 mg, 3.44 mmol) and triethylamine (220 μL).The reaction was heated to reflux for 1 h then the solvent removed invacuo and the residue was dissolved in Et₂O and washed with water thenbrine. The organic layer was dried over MgSO₄, filtered and the solventremoved in vacuo to give 782 mg of 162A.

Example 162, Part B[6-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(methylthio)methyl]-2,3-dihydro-1H-inden-1-yl]methylcarbamicacid 1,1-dimethylethyl ester

[0824]

[0825] 162B was prepared from 162A (682 mg, 2.1 mmol) and5-[Bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (495 mg,2.1 mmol) using the same procedure as 156B to give 538 mg (57%).

Example 162, Part C[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]methylcarbamicacid 1,1-dimethylethyl Ester

[0826] 162 was prepared from 162B (538 mg, 1.2 mmol) and 1D (247 mg, 1.2mmol) using the same procedure as 156C to give 269 mg (46%) of the titlecompound. HPLC retention time: 3.466 min (Method A). Mass spec: 488(M+H⁺).

EXAMPLE 163N-[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]-N-methylacetamide

[0827]

Example 163, Part A2-[2,3-Dihydro-3-(methylamino)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0828]

[0829] To 162 (269 mg, 0.55 mmol) was added TFA (10 mL) and the mixturewas stirred at room temperature for 3 h. The TFA was removed in vacuoand 1N HCl was added. The solid formed was filtered rinsed with 1N HCland dried under vacuum to give 164.5 mg (70.5%)of 163A as an HCl salt.

Example 163, Part BN-[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]-N-methylacetamide

[0830] To 163A (20 mg, 0.052 mmol) in DMF (1.5 mL) with Et₃N (18 μL,0.13 mmol) cooled in a −10° C. bath was slowly added acetylchloride (3.7μL, 0.052 mmol) dissolved in CH₂Cl₂ (0.5 mL). The reaction was stirredat −10° C. for 1 h then the solvent was removed in vacuo and the residuedissolved in CH₂Cl₂ and washed with water and brine. The organic phasewas dried over MgSO₄ filtered and the solvent removed in vacuo to give6.5 mg. HPLC retention time: 2.769 min (Method A). Mass spec: 430(M+H⁺).

EXAMPLE 164N-[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]-2-methoxy-N-methylacetamide

[0831]

[0832] 164 was prepared from 163A (20 mg, 0.052 mmol) and methoxyacetylchloride (4.7 μL, 0.052 mmol) using the same procedure as 163 togive 20.4 mg of the title compound. HPLC retention time: 2.752 min(Method A). Mass spec: 460 (M+H⁺).

EXAMPLE 165N-[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]-N-methyl-1H-imidazole-1-acetamide

[0833]

[0834] To 163A (20 mg, 0.052 mmol) in DMF (1.5 mL) with Et₃N (18 μL,0.13 mmol) cooled in a −10° C. bath was slowly addedchloroacetylchloride (4.1 μL, 0.052 mmol) dissolved in CH₂Cl₂ (0.5 mL).The reaction was stirred at −10° C. for 1 h then imidazole (7 mg, 0.1mmol) and K₂CO₃ (21.5 mg, 0.156 mmol) and the reaction was heated to 60°C. for 1 h. The solvent was removed in vacuo and the residue purified bypreparative chromatography to give 3.8 mg of the title compound. HPLCretention time: 2.539 min (Method A). Mass spec: 496 (M+H⁺).

EXAMPLE 166N-[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]-N-methyl-4-morpholineacetamide

[0835]

[0836] 166 was prepared from 163A (20 mg, 0.052 mmol) and morpholine(10.3 μL, 0.1 mmol) using the same procedure as 165 to give 0.9 mg ofthe title compound. HPLC retention time: 2.526 min (Method A). Massspec: 515 (M+H⁺).

EXAMPLE 167N-[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]-N-methyl-2H-1,2,3-triazole-2-acetamide

[0837]

[0838] 157 was prepared from 163A (39.7 mg, 0.102 mmol) and triazole(17.7 mg, 0.256 mmol) using the same procedure as 165 to give 7.8 mg ofthe title compound. HPLC retention time: 2.726 min (Method A). Massspec: 497 (M+H⁺).

EXAMPLE 168N-[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]-N-methyl-1H-1,2,3-triazole-1-acetamide

[0839]

[0840] 168 was prepared from 163A (39.7 mg, 0.102 mmol) and triazole(17.7 mg, 0.256 mmol) using the same procedure as 165 to give 15.4 mg ofthe title compound. HPLC retention time: 2.659 min (Method A). Massspec: 497 (M+H⁺).

EXAMPLE 169[6-[1,4-Dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-yl]methylcarbamicAcid Ethyl Ester

[0841]

[0842] 169 was prepared from 163A (25 mg, 0.059 mmol) andethylchloroformate (5.6 μL, 0.059 mmol) using the same procedure as 164to give 2.8 mg of the title compound. HPLC retention time: 3.202 min(Method A). Mass spec: 460 (M+H⁺).

EXAMPLE 170 Dimethylcarbamic Acid6-[1,4-dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-2,3-dihydro-1H-inden-1-ylEster

[0843]

[0844] To 163A (15 mg, 0.04 mmol) in DMF (1 mL) was added NaH (2.4 mg,0.1 mmol) at room temperature. The mixture was stirred for 10 min thencooled in −78° C. bath and dimethylcarbamyl chloride (3.7 μL, 0.04 mmol)in DMF (1 mL) was added. The reaction was slowly brought to roomtemperature and stirred for 18 h. The reaction was quenched with 1 dropof acetic acid and the solvent removed in vacuo. Water was added and theprecipitate filtered and rinsed with water to give 11.3 mg. HPLCretention time: 3.108 min (Method A). Mass spec: 446 (M+H⁺).

EXAMPLE 1712-[2,3-Dihydro-1-(1-pyrrolidinyl)-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)-4(1H)-quinolinone

[0845]

[0846] This compound was prepared analogous to 127 starting from5-bromo-1-chloro-indane and using pyrrolidine instead of dimethylamine.LC-MS: HPLC conditions A, retention time=2.53 minutes, m/z 428.15(M+H)⁺.

EXAMPLE 1724-Acetyl-6-[1,4-dihydro-7-methoxy-6-(5-oxazolyl)-4-oxo-2-quinolinyl]-3,4-dihydro-2H-1,4-benzoxazine

[0847]

[0848] This compound was prepared in an analogous fashion to method C2.LC-MS: HPLC conditions E, retention time =2.72 minutes, m/z 418.12(M+H)⁺.

EXAMPLE 1731,2,3,4-Tetrahydro-6-methoxy-7-(5-oxazolyl)-9H-cyclopenta[b]quinolin-9-one

[0849]

[0850] This compound was prepared in an analogous fashion to method A2.LC-MS: HPLC conditions E, retention time=2.25 minutes, m/z 283.15(M+H)⁺.

EXAMPLE 1747-Methoxy-2-[4-(4-morpholinylmethyl)phenyl]-6-(5-oxazolyl)-4(1H)-quinolinone

[0851]

[0852] This compound was prepared in an analogous fashion to method A3.LC-MS: HPLC conditions E, retention time=1.86 minutes, m/z 418.23(M+H)⁺.

[0853] Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed is:
 1. A method of treating inosine monophosphatedehydrogenase associated disorders comprising: administering atherapeutically effective amount of a compound of formula (I)

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein: X¹ is C═O, —S(O)—, or —S(O)₂—; X² is CR³ or N; X³ is —NH—, —O—,or —S—; X⁴ is CR⁴ or N; X⁵ is CR⁵ or N; X⁶ is CR⁶ or N; R¹ is alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, NR⁸R⁹, SR²⁰, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heterocycloalkyl, or heteroaryl; R² is halogen, cyano,nitro, hydroxy, oxo (double bond is no longer present between CR² andX⁶), SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, or heteroaryl; R³is hydrogen, hydroxy, halogen, cyano, CO₂R⁷, NR⁸R⁹, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl or heteroaryl; R⁴, R⁵, and R⁶ are independentlyselected from the group consisting of hydrogen, halogen, nitro, cyano,O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹,C(O)alkyl, C(O)substituted alkyl, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl; R⁷, R¹⁰, and R¹¹,are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl,C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl, C(O) substitutedcycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstitutedalkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl,heterocycloalkyl and heteroaryl; R⁸ and R⁹ are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O)alkyl,C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl,C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl,C(O)heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl,heterocycloalkyl, and heteroaryl or R⁸ and R⁹ taken together with thenitrogen atom to which they are attached complete a heterocycloalkyl orheteroaryl ring; R²⁰ is alkyl, substituted alkyl, cycloalkyl, aryl,substituted aryl, heteroaryl or heterocycloalkyl; R³ and R¹ may be takentogether with the carbon atoms to which they are attached to form amonocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms;and R⁴ and R⁵ may be joined together by the chain —O—CH₂—O— or—O—CH₂—CH₂—O—.
 2. A method of claim 1 comprising: administering atherapeutically effective amount of a compound of formula (II)

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein: R² is a monocyclic substituted or unsubstituted heteroarylgroup.
 3. A method of claim 2 comprising: administering atherapeutically effective amount of a compound of formula (III)

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein: R² is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, orsubstituted 5-oxazolyl; R³ is hydrogen, hydroxy, NR⁸R⁹, alkyl of 1 to 4carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons,substituted alkyl of 1 to 4 carbons, phenyl, substituted phenyl,cycloalkyl of 5 to 7 carbons, substituted cycloalkyl of 5 to 7 carbons,monocyclic heterocycloalkyl and monocyclic heteroaryl; R⁴ is hydrogen,halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF₃, OCF₃,OCH₃, SCH₃, S(O)CH₃, or S(O)₂CH₃; R⁵ is hydrogen, halogen, nitro,hydroxy, alkyl of 1 to 4 carbons, cyano, vinyl, CF₃, CF₂CF₃, CH═CF₂,OCH₃, OCF₃, OCHF₂, SCH₃, S(O)CH₃, or S(O)₂CH₃; and R⁶ is hydrogen,halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF₃, OCH₃,OCF₃, SCH₃, S(O)CH₃, and S(O)₂CH₃.
 4. A method of claim 3 comprising:administering a therapeutically effective amount of a compound includingisomers, enantiomers, diastereomers, tautomers, pharmaceuticallyacceptable salts, prodrugs and solvates wherein: R² is 4-oxazolyl,substituted 4-oxazolyl, 5-oxazolyl, substituted 5-oxazolyl orheteroaryl; R³ is hydrogen, hydroxy, halogen, methyl or NR⁸R⁹; R⁴ ishydrogen; R⁵ is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMeor OCF₃; and R⁶ is hydrogen.
 5. A method of claim 4 comprising:administering a therapeutically effective amount of a compound includingisomers, enantiomers, diastereomers, tautomers, pharmaceuticallyacceptable salts, prodrugs and solvates wherein: R² is 4-oxazolyl,substituted 4-oxazolyl, 5-oxazolyl or substituted 5-oxazolyl; R³ ishydrogen, hydroxy, halogen or methyl; R⁴ is hydrogen; R⁵ is halogen,methyl or OMe; and R⁶ is hydrogen.
 6. A method of treating inosinemonophosphate dehydrogenase associated disorders comprising:administering a therapeutically effective amount of a phosphodiesteraseType 4 inhibitor and a compound of formula (X):

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein: X¹ is C═O, —S(O)—, or —S(O)₂—; X² is CR³ or N; X³ is —NH—, —O—,or —S—; X⁴ is CR⁴ or N; X⁵ is CR⁵ or N; X 6is CR⁶ or N; R¹ is alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, NR⁸R⁹, SR²⁰, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heterocycloalkyl, or heteroaryl; R² is halogen, cyano,nitro, hydroxy, oxo (double bond is no longer present between CR² andX⁶), SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, or heteroaryl; R³is hydrogen, hydroxy, halogen, cyano, CO₂R⁷, NR⁸R⁹, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl or heteroaryl; R⁴, R⁵, and R⁶ are independentlyselected from the group consisting of hydrogen, halogen, nitro, cyano,O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹,C(O)alkyl, C(O)substituted alkyl, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl; R⁷, R¹⁰ and R¹¹,are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl,C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl, C(O) substitutedcycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstitutedalkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl,heterocycloalkyl and heteroaryl; R⁸ and R⁹ are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O)alkyl,C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl,C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl,C(O)heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl,heterocycloalkyl, and heteroaryl or R⁸ and R⁹ taken together with thenitrogen atom to which they are attached complete a heterocycloalkyl orheteroaryl ring; R²⁰ is alkyl, substituted alkyl, cycloalkyl, aryl,substituted aryl, heteroaryl or heterocycloalkyl; R³ and R¹ may be takentogether with the carbon atoms to which they are attached to form amonocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms;and R⁴ and R⁵ may be joined together by the chain —O—CH₂—O— or—O—CH₂—CH₂—O—.
 7. A method for the treatment or prevention of allograftrejection comprising: administering a therapeutically effective amountof a phosphodiesterase Type 4 inhibitor and a compound of formula (X):

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein: X¹ is C═O, —S(O)—, or —S(O)₂—; X² is CR or N; X³ is —NH—, —O—,or —S—; X⁴ is CR⁴ or N; X⁵ is CR⁵ or N; X⁶ is CR⁶ or N; R¹ is alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, NR⁸R⁹, SR²⁰, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heterocycloalkyl, or heteroaryl; R² is halogen, cyano,nitro, hydroxy, oxo (double bond is no longer present between CR² andX⁶), SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, or heteroaryl; R³is hydrogen, hydroxy, halogen, cyano, CO₂R⁷, NR⁸R⁹, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl or heteroaryl; R⁴, R⁵, and R⁶ are independentlyselected from the group consisting of hydrogen, halogen, nitro, cyano,O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷, SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹,C(O)alkyl, C(O)substituted alkyl, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl; R⁷, R¹⁰, and R¹¹,are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl,C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl, C(O) substitutedcycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstitutedalkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl,heterocycloalkyl and heteroaryl; R⁸ and R⁹ are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O)alkyl,C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl,C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl,C(O)heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl,heterocycloalkyl, and heteroaryl or R⁸ and R⁹ taken together with thenitrogen atom to which they are attached complete a heterocycloalkyl orheteroaryl ring; R²⁰ is alkyl, substituted alkyl, cycloalkyl, aryl,substituted aryl, heteroaryl or heterocycloalkyl; R³ and R¹ may be takentogether with the carbon atoms to which they are attached to form amonocyclic or substituted monocyclic ring system of 5 or 6 carbon atoms;and R⁴ and R⁵ may be joined together by the chain —O—CH₂—O— or—O—CH₂—CH₂—O—.
 8. A method of claim 6 wherein: the phosphodiesteraseType 4 inhibitor is Rolipram.
 9. A method of claim 6 wherein: thephosphodiesterase Type 4 inhibitor is[4-[3-(cyclopentyloxy)-4-methoxy-phenyl]-2-pyrrolidinone].
 10. Acompound of formula (I)

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein: X¹ is C═O, —S(O)—, or —S(O)₂—; X² is CR or N; X³ is —NH—, —O—,or —S—; X⁴ is CR⁴ or N; X⁵ is CR⁵ or N; X⁶ is CR⁶ or N; R¹ is alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heterocycloalkyl, or heteroaryl; R² is cyano, hydroxy, oxo (double bondis no longer present between CR² and X⁶), SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁸R⁹,CO₂R⁷ ₁ C(O)NR⁸R⁹, or heteroaryl; R³ is hydrogen, hydroxy, halogen,cyano, CO₂R⁷, NR⁸R⁹, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heterocycloalkyl or heteroaryl; R⁴,R⁵, and R⁶ are independently selected from the group consisting ofhydrogen, halogen, nitro, cyano, O—R⁷, NR⁸R⁹, SR⁷, S(O)R⁷, SO₂R⁷, SO₃R⁷,SO₂NR⁸R⁹, CO₂R⁷, C(O)NR⁸R⁹, C(O)alkyl, C(O)substituted alkyl, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substitutedalkynyl; R⁷ ₁ R¹⁰, and R¹¹, are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,cycloalkyl, substituted cycloalkyl, C(O)alkyl, C(O)substituted alkyl,C(O)cycloalkyl, C(O) substituted cycloalkyl, C(O)aryl, C(O)substitutedaryl, C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)heterocycloalkyl,C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl;R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, alkynyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl,C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl,C(O)Osubstituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl,substituted aryl, heterocycloalkyl, and heteroaryl or R⁸ and R⁹ takentogether with the nitrogen atom to which they are attached complete aheterocycloalkyl or heteroaryl ring; R³ and R¹ may be taken togetherwith the carbon atoms to which they are attached to form a monocyclic orsubstituted monocyclic ring system of 5 or 6 carbon atoms; and R⁴ and R⁵may be joined together by the chain —O—CH₂—O— or —O—CH₂—CH₂—O—; with thefollowing provisos: (c) when X¹ is C═O, X² is CR³, X³ is NH, X⁴ is CR⁴,X⁵ is CR⁵, X⁶ is CR⁶, R¹ is substituted or meta unsubstituted phenyl, R³is H, R⁴ is H, R⁵ is H and R⁶ is H, then R² is not PhCONH,

(d) when X¹ is C═O, S² is CR³, X³ is NH, X⁴ is CR⁴, X⁵ is CR⁵, X⁶ isCR⁶, R¹ is phenyl substituted with H, F, Cl, Br, I, CH₃, CF₃, OH, OCH₃,OCF₃, OCH₂CH₃, NH₂, NHCH₃, N(CH₃)₂, O-benzyl, —C(═O)—R₀, or —C(═O)—OR₀and R₀ is a lower alkyl group, R³ is H, R⁴ is H, R⁵ is H and R⁶ is H,then R² is not

 where Y is CH₂, O or S, m and n are each greater than 1, and the sum ofm and n is between 3 and 6; and (c) when R² is heteroaryl, at least oneof the heteroatoms must be O;
 11. A compound of claim 10 of formula (II)

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein: R² is a monocyclic substituted or unsubstituted heteroarylgroup.
 12. A compound of claim 11 of formula (III)

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates thereofwherein: R is 4-oxazolyl, substituted 4-oxazolyl, 5-oxazolyl, orsubstituted 5-oxazolyl; R³ is hydrogen, hydroxy, NR⁸R⁹, alkyl of 1 to 4carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons,substituted alkyl of 1 to 4 carbons, phenyl, substituted phenyl,cycloalkyl of 5 to 7 carbons, substituted cycloalkyl of 5 to 7 carbons,monocyclic heterocycloalkyl and monocyclic heteroaryl; R⁴ is hydrogen,halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF₃, OCF₃,OCH₃, SCH₃, S(O)CH₃, or S(O)₂CH₃; R⁵ is hydrogen, halogen, nitro,hydroxy, alkyl of 1 to 4 carbons, cyano, vinyl, CF₃, CF₂CF₃, CH═CF₂,OCH₃, OCF₃, OCHF₂, SCH₃, S(O)CH₃, or S(O)₂CH₃; and R⁶ is hydrogen,halogen, nitro, hydroxy, alkyl of 1 to 4 carbons, cyano, CF₃, OCH₃,OCF₃, SCH₃, S(O)CH₃, and S(O)₂CH₃.
 13. A compound of claim 12 includingisomers, enantiomers, diastereomers, tautomers, pharmaceuticallyacceptable salts, prodrugs and solvates wherein: R² is 4-oxazolyl,substituted 4-oxazolyl, 5-oxazolyl, substituted 5-oxazolyl orheteroaryl; R³ is hydrogen, hydroxy, halogen, methyl or NR⁸R⁹; R⁴ ishydrogen; R⁵ is halogen, methyl, ethyl, substituted alkenyl, alkyne, OMeor OCF₃; and R⁶ is hydrogen.
 14. A compound of claim 13 includingisomers, enantiomers, diastereomers, tautomers, pharmaceuticallyacceptable salts, prodrugs and solvates wherein: R² is 4-oxazolyl,substituted 4-oxazolyl, 5-oxazolyl or substituted 5-oxazolyl; R³ ishydrogen, hydroxy, halogen or methyl; R⁴ is hydrogen; R⁵ is halogen,methyl or OMe; and R⁶ is hydrogen.
 15. A compound of claim 10 of formula(V)

including isomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, prodrugs and solvates selected from:a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R¹ is hydrogen; a compound of formula (V) wherein: R¹ is CH₃ and R³is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is CH₃; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³is hydrogen; a compound of formula (V) wherein: R¹ is

and R ³is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is Br; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; a compound of formula (V) wherein: R¹ is

and R³ is hydrogen; and a compound of formula (V) wherein: R¹ is

and R³ is hydrogen.
 16. A compound of claim 10 including isomers,enantiomers, diastereomers, tautomers, pharmaceutically acceptablesalts, prodrugs and solvates thereof selected from:


17. A pharmaceutical composition comprising a compound of claim 10 and apharmaceutically acceptable carrier.
 18. A pharmaceutical compositioncomprising a compound of claim 11 and a pharmaceutically acceptablecarrier.
 19. A pharmaceutical composition comprising a compound of claim12 and a pharmaceutically acceptable carrier.
 20. A pharmaceuticalcomposition comprising a compound of claim 13 and a pharmaceuticallyacceptable carrier.
 21. A pharmaceutical composition comprising acompound of claim 14 and a pharmaceutically acceptable carrier.
 22. Apharmaceutical composition comprising a compound of claim 15 and apharmaceutically acceptable carrier.
 23. A pharmaceutical compositioncomprising a compound claim 16 and a pharmaceutically acceptablecarrier.
 24. A method of treating inosine monophosphate dehydrogenaseassociated disorders comprising: administering an therapeuticallyeffective amount of the composition of claim
 17. 25. A method oftreating inosine monophosphate dehydrogenase associated disorderscomprising: administering a therapeutically effective amount of thecomposition of claim 17 and another agent known to be useful intreatment of such disorders.
 26. A method of treating inosinemonophosphate dehydrogenase associated disorders comprising:administering a therapeutically effective amount of the pharmaceuticalcomposition of claim 17 and a phosphodiesterase Type 4 inhibitor.
 27. Amethod for the treatment or prevention of allograft rejectioncomprising: administering a therapeutically effective amount of thepharmaceutical composition of claim 17 and a phosphodiesterase Type 4inhibitor.
 28. A method of claim 7 wherein: the phosphodiesterase Type 4inhibitor is Rolipram.
 29. A method of claim 7 wherein: thephosphodiesterase Type 4 inhibitor is[4-[3-(cyclopentyloxy)-4-methoxy-phenyl]-2-pyrrolidinone].